EP3592376A1 - Vorrichtung und verfahren zur verabreichung einer nauseogenen verbindung aus einer arzneimittelabgabevorrichtung - Google Patents

Vorrichtung und verfahren zur verabreichung einer nauseogenen verbindung aus einer arzneimittelabgabevorrichtung

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Publication number
EP3592376A1
EP3592376A1 EP18712409.4A EP18712409A EP3592376A1 EP 3592376 A1 EP3592376 A1 EP 3592376A1 EP 18712409 A EP18712409 A EP 18712409A EP 3592376 A1 EP3592376 A1 EP 3592376A1
Authority
EP
European Patent Office
Prior art keywords
nauseogenic
nauseogenic compound
subject
compound
delivery device
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP18712409.4A
Other languages
English (en)
French (fr)
Inventor
Andrew Young
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
I2O Therapeutics Inc
Original Assignee
Intarcia Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Intarcia Therapeutics Inc filed Critical Intarcia Therapeutics Inc
Publication of EP3592376A1 publication Critical patent/EP3592376A1/de
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • Drugs administered orally or by injection generally undergo rapid absorption phase during which drug concentrations in plasma reach Cmax, followed by an elimination phase during which drug concentrations in plasma fall (See Figure 1 A). Before drug concentrations in plasma fall below a minimum effective concentration (MEC) a subsequent dose is administered to maintain plasma concentrations of drug within a therapeutic range. Multiple administered doses yield plasma concentrations of drug exhibiting numerous peaks and troughs as concentrations of the drug periodically rise and fall (See Figures 2-8).
  • Applicant has discovered benefits of administration of certain nauseogenic compounds, such as long-acting nauseogenic peptides, via certain drug delivery devices, particularly implantable osmotic drug delivery devices.
  • Administration of certain long-acting nauseogenic peptides from an implantable osmotic drug delivery device can be configured to provide incremental absorption of the nauseogenic compound so that it slowly and gradually reaches mean steady state concentration (Css) in plasma. Further, mean Css is steadily maintained without undergoing an elimination phase and thus without incurring substantial peaks and troughs in plasma concentrations (See Figure IB).
  • Applicant has further discovered that certain long-acting nauseogenic peptides, having affinity to albumin and prolonged elimination half-lives in humans, are particularly amenable to the disclosed methods of administration via an implantable osmotic drug delivery device.
  • nausea and vomiting from administration of certain nauseogenic compounds can be curtailed or eliminated upon continuous administration from an implantable drug delivery device that (i) provides gradual absorption of the nauseogenic compound, via slow and steady ramp-up, as it reaches and maintains mean steady state concentration (Css); (ii) maintains mean Css in plasma for weeks, months, one year or longer, substantially free from an elimination phase and thus without incurring substantial peaks and troughs in plasma concentration; and (iii) minimizes, to the extent possible during (i) and (ii), rate of change, particularly positive rate of change, in plasma concentration over time, expressed herein alternatively as dfnauseogenic compound] /dt or d[drugj/dt.
  • Css mean steady state concentration
  • nausea and vomiting can be curtailed when rate of change in plasma concentration of the nauseogenic compound is minimized during course of treatment.
  • nausea and vomiting can be curtailed when positive rate of change in plasma concentration, dfnauseogenic compoundj/dt, is held to less than about +2% per hour of the mean steady state concentration (Css) of the nauseogenic compound during the course of treatment.
  • Css mean steady state concentration
  • an apparatus comprising a drug delivery device and a nauseogenic compound, configured to provide, upon being contacted with a subject: administration of a dose of the nauseogenic compound to the subject; wherein during the first 24 hours following initiation of administration, less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject; and, once Css is attained, Css of the nauseogenic compound is maintained in the plasma of the subject for at least two weeks.
  • Css mean steady state concentration
  • a related method for treating a subject comprising contacting the subject with a drug delivery device comprising a nauseogenic compound, wherein the drug delivery device administers the nauseogenic compound to the subject, and the contacting occurs after an administration of the drug delivery device comprising the nauseogenic compound to a human patient population during a first clinical trial; and wherein less than 10% of the human patient population, to whom the drug delivery device comprising the nauseogenic compound was administered, reported having nausea and/or vomiting during the first clinical trial.
  • a related method for treating a subject comprising contacting the subject with a drug delivery device comprising a nauseogenic compound and the drug delivery device administers the nauseogenic compound to the subject, wherein incidence of nausea and/or vomiting is 10% or less during a first clinical trial regarding administration of the drug delivery device comprising a continuous dose of the nauseogenic compound to a first human patient population; and incidence of nausea and/or vomiting is 15% or greater during a second clinical trial regarding administration of an injectable or oral dose of the nauseogenic compound to a second human patient population.
  • a related method for treating a subject comprising contacting the subject with a drug delivery device comprising a nauseogenic compound and the drug delivery device administers the nauseogenic compound to the subject, wherein incidence of nausea and/or vomiting, reported as a percentage of a first human patient population, during a first clinical trial regarding administration of the drug delivery device comprising a continuous dose of the nauseogenic compound to the first human patient population is reduced by at least 20% relative to incidence of nausea and/or vomiting, reported as a percentage of a second human patient population, during a second clinical trial regarding an administration of an injectable or an oral dose of the nauseogenic compound to the second human patient population.
  • a related method for treating a subject comprising contacting the subject with a drug delivery device comprising a dose of a nauseogenic compound, wherein the drug delivery device administers the nauseogenic compound to the subject, during the first 24 hours following initiation of administration, less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject; and once Css is attained, Css of the nauseogenic compound is maintained in the plasma of the subject for at least two weeks and dfnauseogenic compound] /dt is held to less than about +2% per hour of the mean steady state concentration (Css) of the nauseogenic compound.
  • Css mean steady state concentration
  • Figure 1 A is a plot illustrating human plasma concentrations of a hypothetical drug administered orally or by injection. Shown is a rapid absorption phase during which drug concentrations in plasma reach Cmax, followed by an elimination phase during which drug concentrations in plasma fall. Before drug concentrations in plasma fall below a minimum effective concentration (MEC) a subsequent dose is administered to maintain plasma concentrations of drug within a therapeutic range below a minimum toxic concentration (MTC) and above the MEC. See, for example, Figures 2-8.
  • MEC minimum effective concentration
  • MTC minimum toxic concentration
  • Figure IB is a plot illustrating target non-continuous infusion rates for a nauseogenic compound administered via a drug delivery device, estimated to minimize nausea and/or vomiting relative to oral or injectable administration. Ideal ramp-up should be slow, steady and approach a (Css) plateau in ⁇ 4 weeks (t1 ⁇ 2 -10 days). Eventual plasma concentrations of the nauseogenic compound may be e.g., 6x initial plasma concentrations.
  • such target rates are achieved with certain long-acting nauseogenic peptides via continuous administration of a predetermined rate at a fixed dose from an implantable osmotic drug delivery device, rather than by increasing the provided dosage from low to high.
  • plasma concentrations of the nauseogenic compound gradually increase to Css.
  • Figure 2 is a plot illustrating human plasma concentrations of exenatide administered via periodic injection (BID aqueous solution). Daily dosing is made possible by peptidase resistance of exenatide. Tmax - 1.3 hours; t1 ⁇ 2 -3.2 hours (by contrast, peptidase prone GLP-1 t1 ⁇ 2 -3.4 min); peak-trough 82% of peak; peak 1.8x mean; d[drug]/dt 62% mean/hour; 40-41% nausea, 13-18% vomiting in 16-30 weeks.
  • Figure 3 is a plot illustrating human plasma concentrations of lixisenatide administered via periodic injection (daily aqueous solution). Daily dosing is made possible by peptidase resistance of lixisenatide. Tmax - 1.7 hours. t1 ⁇ 2 -3.0 hours; peak-trough 97% of peak; peak 2.4x mean; d[drug]/dt 204% mean/hour; 26% nausea, 11% vomiting in 24 weeks.
  • Figure 4 is a plot illustrating human plasma concentrations of liraglutide administered via periodic injection (daily aqueous solution). Daily dosing is made possible by binding of liraglutide to albumin, avoiding clearance by renal filtration. Tmax - 12 hours; peak- trough 39% of peak; peak 1.2x mean; d[drug]/dt 11% of mean/hour; nausea 28%, vomiting 11% in 52 weeks.
  • Figure 5 is a plot illustrating human plasma concentrations of semaglutide administered via periodic injection (weekly aqueous solution). Daily dosing is made possible by high affinity binding of semaglutide to albumin. Tmax - 3.2 days. Weekly dosing is made possible by high albumin affinity, t1 ⁇ 2 -8.3 days; peak-trough 26% of peak; peak 1.12x mean; d[drug]/dt; 3.3% mean/hour; nausea reported 22%, withdrawn 6%.
  • Figure 6 is a plot illustrating human plasma concentrations of dulaglutide, albiglutide, and exendin-4 AlbudAb, administered via periodic injection (weekly aqueous solution). Peak-trough: dulaglutide 63% of peak, albiglutide 28% of peak, exendin-4 AlbudAb 31% of peak.
  • Figure 7 is a plot illustrating human plasma concentrations of exenatide (Bydureon, poly(lactic-co-gly colic acid (PLGA) encapsulation) following administration of a single bolus injection. Shown is the triphasic release pattern, including a sizeable burst, with maximum release rate -2 months. Max d[drug]/dt 63% of mean/hour.
  • exenatide Bodureon, poly(lactic-co-gly colic acid (PLGA) encapsulation
  • Plasma concentrations reported for a single subcutaneous bolus of exenatide formulated within PLGA matrix are shown as the symbols.
  • the tri-phasic release comprised an initial burst followed by periods of accelerated release at 2 and 8 weeks after administration.
  • the profile was modeled as the sum of 3 gaussian curves distributed along a logarithmic time domain (X-axis).
  • Figure 8 is a plot illustrating human plasma concentrations of exenatide (Bydureon, PLGA encapsulation) administered via periodic injection (weekly aqueous solution). Weekly stacking of triphasic release profiles results in peak-trough 9.9% of peak; peak 1. lx mean; max d[drug]/dt 4.4% of mean/hour; nausea 11.3%, vomiting ⁇ 5% over 26 weeks.
  • Figure 9 is a plot illustrating human plasma concentrations of exenatide (nonaqueous formulation) administered via single subdermal placement of an ITCA-650 osmotic drug delivery device. In contrast to human plasma concentrations illustrated in the plots of Figures 2-8, the plot of Figure 9 attains a single peak and does not exhibit peak-trough oscillations in mean plasma concentrations.
  • Figure 10 is a summary plot depicting incidence of patients reporting nausea vs. d[drug]/dt for periodic injection of the aqueous formulations of Figures 2-8 and for exenatide administered via single subdermal placement of an ITCA-650 osmotic drug delivery device of Figure 9.
  • Figure 11 A is a plot estimating mean ss over time for liraglutide and semaglutide if administered via single subdermal placement of an osmotic drug delivery device. Comparison is made with mean ss over time for exenatide administered via single subdermal placement of an ITCA-650 osmotic drug delivery device (as shown in Figure 9).
  • Figure 1 IB is a plot comparing estimated d[drug]/dt for exenatide, liraglutide and semaglutide if administered via single subdermal placement of an osmotic drug delivery device.
  • d[semaglutide]/dt is 35x lower than d[exenatide]/dt if administered via single subdermal placement of an osmotic drug delivery device.
  • Figure 12 is a summary plot estimating incidence of patients reporting nausea vs. d[drug]/dt for compounds of Figures 2-8 and for exenatide of Figure 9 if each is administered via single subdermal placement of an osmotic drug delivery device.
  • FIG. 13 is an illustrative model of the pharmacokinetics of subcutaneously (SC) administered GLP-1 agonists.
  • SC subcutaneously
  • Central Central compartments
  • a constant fraction of SC drug enters the Central compartment per unit time (defined by Ka).
  • a constant fraction of Central drug is eliminated per unit time (defined by K).
  • Central drug concentration (equal to plasma drug concentration) is an amount of drug in the Central compartment (A) diluted into its volume of distribution (Vd).
  • Figure 14 is a plot comparing potencies of liraglutide and semaglutide at human GLP-1 receptors based upon final albumin concentration in the incubations. Potencies decreased with increasing albumin concentration, with the mid-range of change occurring with an albumin (HSA) concentration of -0.6%.
  • HSA albumin
  • Figure 15 shows three plots comparing potency shifts in 4% vs 0.1% albumin, as determined for human GLP-1 [7-36]NH2 (red), liraglutide (blue) and semaglutide (green). There was a small (1.8-fold) increase in potency for human GLP-1 [7-36]NH2 in 4% albumin. In contrast, there was a 9.3-fold decrease in potency for liraglutide, and a 19.9-fold decrease for semaglutide. Relative to the effect observed with GLP-1 [7-36]NH2, these represent 17.2- and 36.8-fold shifts in potency, respectively, for liraglutide and semaglutide.
  • the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.” [0036] Unless specifically stated or obvious from context, as used herein, the term “substantially” is understood as within a narrow range of variation or otherwise normal tolerance in the art. Substantially can be understood as within 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01% or 0.001% of the stated value.
  • the term "contacting,” with respect to an implantable drug delivery device refers to subdermal placement or insertion of the implantable drug delivery device, such as an implantable osmotic drug delivery device, beneath a surface of skin of a patient.
  • the term "contacting,” with respect to an non-implantable drug delivery device, such as a non-implantable miniaturized patch pump refers to affixing the miniaturized patch pump on an outer surface of skin of a patient.
  • peptide typically refers to a molecule comprising a chain of two or more amino acids (e.g., most typically L-amino acids, but also including, e.g., D-amino acids, modified amino acids, amino acid analogs, and amino acid mimetic).
  • Peptides may be naturally occurring, synthetically produced, or recombinantly expressed. Peptides may also comprise additional groups modifying the amino acid chain, for example, functional groups added via post-translational modification.
  • post-translation modifications include, but are not limited to, acetylation, alkylation (including, methylation), biotinylation, glutamylation, glycylation, glycosylation, isoprenylation, lipoylation, phosphopantetheinylation, phosphorylation, selenation, and C-terminal amidation.
  • the term peptide also includes peptides comprising modifications of the amino terminus and/or the carboxy terminus. Modifications of the terminal amino group include, but are not limited to, des-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications.
  • Modifications of the terminal carboxy group include, but are not limited to, amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications (e.g., wherein lower alkyl is C 1-C4 alkyl).
  • the term peptide also includes modifications, such as but not limited to those described above, of amino acids falling between the amino and carboxy termini.
  • a peptide may be modified by addition of a small-molecule drug.
  • the terms "lower alkyl” and “lower alkoxy” refer to an alkyl or alkoxy group, respectively, having 1-6 carbon atoms.
  • non-aqueous refers to an overall moisture content, for example, of a suspension formulation, typically of less than or equal to about 10 wt %, for example, less than or equal to about 7 wt %, less than or equal to about 5 wt %, and/or less than about 4 wt %. Also, a particle formulation of the present invention comprises less than about 10 wt %, for example, less than about 5 wt %, residual moisture.
  • implantable delivery device typically refers to a delivery device that is fully implanted beneath the surface of a subject's skin to affect administration of a drug.
  • Implantable delivery devices include Hydron® Implant Technology, from Valera Pharmaceuticals. Inc.; NanoGATETM implant, from iMEDD Inc.; MIP implantable pump or DebioStarTM drug delivery technology, from Debiotech S.A.; ProzorTM, NanoporTM or Delos PumpTM, from Delpor Inc.; or an implantable osmotic delivery device, e.g., ITCA-0650, from Intarcia Therapeutics, Inc.
  • osmotic delivery device and “implantable osmotic delivery device” are used interchangeably herein and typically refer to a device used for delivery of a drug (e.g., a nauseogenic compound) to a subject, wherein the device comprises, for example, a reservoir (made, e.g., from a titanium alloy) having a lumen that contains a suspension formulation comprising a drug (e.g., a nauseogenic compound) and an osmotic agent formulation.
  • a piston assembly positioned in the lumen isolates the suspension formulation from the osmotic agent formulation.
  • a semi-permeable membrane is positioned at a first distal end of the reservoir adjacent the osmotic agent formulation and a diffusion moderator (which defines a delivery orifice through which the suspension formulation exits the device) is positioned at a second distal end of the reservoir adjacent the suspension formulation.
  • the osmotic delivery device is implanted within the subject, for example, subdermally or subcutaneously (e.g., in the inside, outside, or back of the upper arm and in the abdominal area).
  • An exemplary osmotic delivery device is the DUROS® (ALZA Corporation, Mountain View, Calif.) delivery device.
  • osmotic delivery device examples include but are not limited to “osmotic drug delivery device”, “osmotic drug delivery system”, “osmotic device”, “osmotic delivery device”, “osmotic delivery system”, “osmotic pump”, “implantable drug delivery device”, “drug delivery system”, “drug delivery device”, “implantable osmotic pump”, “implantable drug delivery system”, and “implantable delivery system”.
  • Other terms for "osmotic delivery device” are known in the art.
  • continuous delivery typically refers to a substantially continuous release of drug from an osmotic delivery device and into tissues near the implantation site, e.g. , subdermal and subcutaneous tissues.
  • an osmotic delivery device releases drug essentially at a predetermined rate based on the principle of osmosis.
  • Extracellular fluid enters the osmotic delivery device through the semi-permeable membrane directly into the osmotic engine that expands to drive the piston at a slow and consistent rate of travel. Movement of the piston forces the drug formulation to be released through the orifice of the diffusion moderator.
  • release of the drug from the osmotic delivery device is at a slow, controlled, consistent rate.
  • the volume of the chamber comprising the drug formulation is between about 100 ⁇ to about 1000 ⁇ , more preferably between about 140 ⁇ and about 200 ⁇ . In one embodiment, the volume of the chamber comprising the drug formulation is about 150 ⁇ .
  • substantially steady-state delivery typically refers to delivery of a drug at or near a target therapeutic concentration over a defined period of time, wherein the amount of the drug being delivered from an osmotic delivery device is substantially zero-order delivery.
  • Substantial zero-order delivery of an active agent e.g., a nauseogenic compound
  • the rate of drug delivered is constant and is independent of the drug available in the delivery system; for example, for zero-order delivery, if the rate of drug delivered is graphed against time and a line is fitted to the data the line has a slope of approximately zero, as determined by standard methods (e.g., linear regression).
  • non-implantable delivery device typically refers to a delivery device, including a “non-implantable miniaturized patch pump,” having certain components that are not implanted beneath the surface of a subject's skin to affect administration of a drug.
  • Representative non-implantable delivery devices include patch pumps
  • MedSolve Technologies, Inc. Medipacs pump, from Medipacs, Inc.; Medtronic pump and MiniMed Paradigm, from Medtronic, Inc.; NanopumpTM, from Debiotech S.A. and STMicroelectronics; NiliPatch pump, from NiliMEDIX Ltd.; PassPort ® , from Altea Therapeutics Corp.; Steady Med patch pump, from Steady Med Ltd.; V-GoTM, from Valeritas, Inc.; Finesse, from LifeScan; JewelPUMPTM, from Debiotech S.A.; SmartDose Electronic Patch Injector, from West Pharmaceutical Services, Inc.; SenseFlex FD (disposable) or SD (semi-disposable), from Sensile Medical A.G.; Asante Snap, from Bigfoot Biomedical; PicoSulin device, from PicoSulin; and Animas ® OneTouch Ping Pump, from Animas Corp.
  • the non-implantable miniaturized patch pump is, e.g., JewelPUMPTM (Debiotech S.A.), placed on the surface of the skin. Dosing of the JewelPUMPTM device is adjustable and programmable.
  • mean steady state concentration (Css) in plasma of a short-acting nauseogenic compound can gradually be attained, via slow ramp-up of an increasing dosage, in the subject over days, weeks or months.
  • mean steady state concentration (Css) in plasma of a long-acting nauseogenic compound can gradually be attained, via slow ramp-up of an increasing dosage and/or via continuous administration of a fixed dose, in the subject over days, weeks or months.
  • the jewelPUMPTM is a miniaturized patch-pump based on a microelectromechanical system (MEMS) with a disposable unit having payload for ultra-precise administration of compound.
  • the disposable unit is filled once with compound and discarded after use, while the controller unit (including the electronics) can be used for 2 years with multiple disposable units.
  • the jewelPUMPTM is detachable, watertight for bathing and swimming, includes direct access bolus buttons and a discreet vibration & audio alarm on the patch-pump.
  • the jewelPUMPTM is remotely controlled.
  • the delivery device is an MEMS-containing non-implantable delivery device, e.g., carried by the patient or placed on the surface of the skin.
  • the delivery device is an MEMS- containing implantable delivery device.
  • drug half-life or "ti/ 2 " as used herein refers how long it takes a drug to be eliminated from blood plasma by one half of its concentration.
  • a drug's half-life is usually measured by monitoring how a drug degrades when it is administered via injection or intravenously.
  • a drug is usually detected using, for example, a radioimmunoassay (RIA), a chromatographic method, an electrochemiluminescent (ECL) assay, an enzyme linked immunosorbent assay (ELISA) or an immunoenzymatic sandwich assay (IEMA).
  • RIA radioimmunoassay
  • ECL electrochemiluminescent
  • ELISA enzyme linked immunosorbent assay
  • IEMA immunoenzymatic sandwich assay
  • serum is meant to mean any blood product from which a substance can be detected.
  • serum includes at least whole blood, serum, and plasma.
  • nauseogenic compound is meant to mean any compound associated with an incidence of nausea and/or vomiting of greater than or equal to 5% in a patient population during at least one clinical trial (e.g., generally referred to herein as a second clinical trail) regarding treatment of a disorder or disease with the nauseogenic compound.
  • a second clinical trail e.g., generally referred to herein as a second clinical trail
  • Certain classes of nauseogenic compounds, including nauseogenic peptides, particularly for treatment of type-2 diabetes, are described in greater detail herein. These and other structurally disparate nauseogenic compounds commonly contribute to an incidence of nausea of equal to or greater than 5% in a patient population during at least one clinical trial.
  • the nauseogenic compound is associated with a higher incidence of nausea and/or vomiting of at least 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, or from 10-20%, 20-30%, 30-40%, 40-50%, 50-75%, 75-100%, in a patient population during at least one clinical trial (e.g., second clinical trail) regarding treatment of a disorder or disease with the nauseogenic compound.
  • a clinical trial e.g., second clinical trail
  • such established nauseogenic compounds when administered according to disclosed methods, are associated with reduced incidence of nausea and/or vomiting, for example, during treatment or a related clinical trail (e.g., generally referred to herein as a first clinical trail) relative to incidence of nausea and/or vomiting described above in the second clinical trail.
  • a related clinical trail e.g., generally referred to herein as a first clinical trail
  • Certain embodiments relate to an incidence of nausea for the nauseogenic compound. Other embodiments relate to an incidence of vomiting for the nauseogenic compound. Some embodiments relate to an incidence of nausea or vomiting for the nauseogenic compound. Some embodiments relate to an incidence of nausea and vomiting for the nauseogenic compound.
  • the terms "incidence of nausea,” “incidence of vomiting” and “incidence of nausea and/or vomiting” as used herein may refer to a percentage of subjects or patients in a patient population that has experienced nausea and/or vomiting, at least once, during a period of time following subcutaneous administration of a nauseogenic compound. For example, an incidence of nausea of 10% in a patient population of 100 patients during a clinical trial lasting 52 weeks, means that 10 patients experienced nausea at least once during the 52 week period.
  • incidence of nausea and/or vomiting is determined from the percentage of patients in a patient population who have experienced nausea and/or vomiting, one or more times, throughout the course of a clinical trial, following oral, injectable, or continuous subcutaneous administration via delivery device of a nauseogenic compound.
  • Incidence of nausea and/or vomiting from administration via delivery device, or oral or injectable administration of a nauseogenic compound can be established, e.g. , from published clinical studies and/or information provided in the product insert of a marketed nauseogenic compound.
  • prevalence of nausea may refer to a percentage of subjects or patients in a patient population that has experienced nausea and/or vomiting, at a particular point in time, following subcutaneous administration of a nauseogenic compound.
  • incidence of nausea and/or vomiting over the course of a clinical trial involves a higher percentage of patients than does prevalence of nausea and/or vomiting at any particular point in time during the clinical trial.
  • prevalence of nausea and/or vomiting is determined at one or more specific time points following subcutaneous administration.
  • prevalence of nausea and/or vomiting is determined after a period of time (e.g.
  • Prevalence of nausea and/or vomiting from administration via delivery device, or oral or injectable administration of a nauseogenic compound can be established, e.g. , from published clinical studies and/or information provided in the product insert of a marketed nauseogenic compound.
  • Incidence and prevalence of adverse events, such as nausea and/or vomiting, during a clinical trial is generally reported for a patient population that has been administered a nauseogenic compound, and these results are compared against those for a placebo group that has not been administered the nauseogenic compound.
  • incidence or prevalence of nausea and/or vomiting is a reported percentage of the patient population regardless of incidence or prevalence of nausea and/or vomiting in a placebo group. In such embodiments, the incidence or prevalence of nausea and/or vomiting in the placebo group is not subtracted from the reported incidence or prevalence of nausea and/or vomiting in the patient population that was administered the nauseogenic compound.
  • incidence or prevalence of nausea and/or vomiting is a reported percentage of the patient population that was administered the nauseogenic compound minus the incidence or prevalence of nausea and/or vomiting in the placebo group.
  • a "short-acting nauseogenic peptide” such as a “short-acting GLP- 1 receptor agonist peptide” is a nauseogenic peptide having an elimination half-life (ti/ 2 ) in humans of less than about 5 hours following subcutaneous administration.
  • long-acting nauseogenic peptide such as a “long-acting GLP-1 receptor agonist peptide” is a nauseogenic peptide having an elimination half-life (tin) in humans of at least about 5 hours following subcutaneous administration. In some embodiments, the nauseogenic peptide has an elimination half-life (tin) in humans of at least about 8 hours, 10 hours, 12 hours, 16 hours, 24 hours or longer following subcutaneous administration.
  • Applicant has discovered benefits of administration of certain nauseogenic compounds via a drug delivery device that is configured to (i) provide gradual absorption of the nauseogenic compound, via slow and steady ramp-up, as it reaches and maintains mean steady state concentration (Css); (ii) maintains mean Css in plasma for weeks, months, one year or longer, substantially free from an elimination phase and thus without incurring substantial peaks and troughs in plasma concentration; and (iii) minimize, to the extent possible during (i) and (ii), rate of change in plasma concentration over time, particularly positive rate of change, expressed herein alternatively as dfnauseogenic compoundj/dt or d[drug]/dt.
  • Css mean steady state concentration
  • Positive rate of change in plasma concentration over time is maximized by occurrence of sudden spikes (i.e., rate increases) or during peak-trough fluctuations in plasma concentration that are generally attributable to periodic oral or injectable administrations.
  • positive rate of change in plasma concentration during treatment is minimized during slow and steady ramp- up of plasma concentration of a nauseogenic compounds in the absence of peak-trough fluctuations, e.g. , according to the methods of administration described herein.
  • Benefits of the methods of administration described herein include reduced or eliminated incidence of nausea and/or vomiting for nauseogenic compounds, particularly relative to oral or injectable administration of the same.
  • a method for treating a subject for type-2 diabetes comprising contacting the subject with an implantable osmotic drug delivery device comprising a long-acting nauseogenic peptide.
  • implantable osmotic drug delivery device comprising a long-acting nauseogenic peptide.
  • Such methods configure the implantable osmotic drug delivery device and long-acting nauseogenic peptide to (i) provide gradual absorption of the nauseogenic compound, via slow and steady ramp-up, as it reaches and maintains mean steady state concentration (Css); (ii) maintain mean Css in plasma for weeks, months, one year or longer; and (iii) minimize, to the extent possible during (i) and (ii), rate of change in plasma concentration over time.
  • Css mean steady state concentration
  • an apparatus comprising a drug delivery device and a nauseogenic compound, configured to provide, upon being contacted with a subject: administration of a dose of the nauseogenic compound to the subject; wherein during the first 24 hours following initiation of administration, less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject; and, once Css is attained, Css of the nauseogenic compound is maintained in the plasma of the subject for at least two weeks.
  • Css mean steady state concentration
  • a related method for treating a subject comprising contacting the subject with a drug delivery device comprising a first dose of a nauseogenic compound, wherein the drug delivery device administers the nauseogenic compound to the subject, and the contacting occurs after an administration of the drug delivery device comprising the nauseogenic compound to a human patient population during a first clinical trial; where less than 10% of the human patient population, to whom the drug delivery device comprising the first dose of the nauseogenic compound was administered, reported having nausea and/or vomiting during the first clinical trial.
  • a nauseogenic compound for use in a method of treating a subject, comprising contacting the subject with a drug delivery device comprising a first dose of the nauseogenic compound, wherein the drug delivery device administers the nauseogenic compound to the subject, and the contacting occurs after an administration of the drug delivery device comprising the nauseogenic compound to a human patient population during a first clinical trial; wherein less than 10% of the human patient population, to whom the drug delivery device comprising the first dose of the nauseogenic compound was administered, reported having nausea and/or vomiting during the first clinical trial.
  • nauseogenic compounds are associated with a high incidence (e.g., at least 5% but sometimes about 10%-15% or 15%-20% or greater than 20%) of nausea and/or vomiting in a patient population during at least one clinical trial (e.g., generally referred to herein as a second clinical trail) regarding treatment of a disorder or disease with the nauseogenic compound.
  • Methods according to the third aspect reduce the incidence of nausea and/or vomiting (e.g., about 10% or less) in a patient population, e.g., as evidenced during at least one clinical trial regarding administration of drug delivery device comprising the first dose of the nauseogenic compound (e.g., generally referred to herein as a first clinical trail).
  • the percentage of human patients who reported having nausea and/or vomiting during the first clinical trial is less than (e.g., 10% to 25% less than, 25% to 50% less than, 50% to 75% less than, 75% to 99% less than) the percentage that reported having nausea and/or vomiting during a second clinical trial regarding an injectable form of the nauseogenic compound.
  • the percentage of human patients who reported having nausea and/or vomiting during the first clinical trial is less than (e.g., 10% to 25% less than, 25% to 50% less than, 50% to 75% less than, 75% to 99% less than) the percentage that reported having nausea and/or vomiting during a second clinical trial regarding an orally available form of the nauseogenic compound.
  • the drug delivery device delivers the nauseogenic compound to the subject. In other embodiments, the drug delivery device provides the nauseogenic compound to the subject.
  • a related method for treating a subject comprising contacting the subject with a drug delivery device comprising a nauseogenic compound and the drug delivery device administers the nauseogenic compound to the subject, wherein incidence of nausea and/or vomiting is 10% or less during a first clinical trial regarding administration of the drug delivery device comprising a continuous dose of the nauseogenic compound to a first human patient population; and incidence of nausea and/or vomiting is 15% or greater during a second clinical trial regarding administration of an injectable or oral dose of the nauseogenic compound to a second human patient population.
  • a nauseogenic compound for use in a method of treating a subject, comprising contacting the subject with a drug delivery device comprising the nauseogenic compound and the drug delivery device administers the nauseogenic compound to the subject, wherein incidence of nausea and/or vomiting is 10% or less during a first clinical trial regarding administration of the drug delivery device comprising a continuous dose of the nauseogenic compound to a first human patient population; and incidence of nausea and/or vomiting is 15% or greater during a second clinical trial regarding administration of an injectable or oral dose of the nauseogenic compound to a second human patient population.
  • nauseogenic compounds are associated with a high incidence (e.g., at least 5% but sometimes about 10%-15% or 15%-20% or greater than 20%) of nausea and/or vomiting in a patient population during at least one clinical trial (e.g., generally referred to herein as a second clinical trail) regarding treatment of a disorder or disease with the nauseogenic compound.
  • Methods according to the fourth aspect reduce the incidence of nausea and/or vomiting (e.g., to about 10% or less) in a patient population, e.g., as evidenced during at least one clinical trial regarding administration of drug delivery device comprising the first dose of the nauseogenic compound (e.g., generally referred to herein as a first clinical trail).
  • first clinical trial and second clinical trial are merely used to distinguish clinical trials and do not imply that the "first clinical trial” was conducted prior to the "second clinical trial.”
  • second clinical trial pertaining to an injectable or oral administration of the nauseogenic compound precedes the "first clinical trial” pertaining to administration with a drug delivery device comprising a nauseogenic compound.
  • first human patient population and second human patient population are merely used to distinguish human patient populations and do not imply that the "first human patient population” was treated or administered the nauseogenic compound prior to administration to the "second human patient population.”
  • clinical trial refers to any medical study of a human patient population of between ten and ten thousand patients, at least some of whom have been administered (e.g., orally, via injection or upon continuous subcutaneous administration via delivery device) a nauseogenic compound for the treatment of any disease or disorder such as diabetes, e.g., type-2 diabetes, obesity or any of the "variety of conditions" described herein.
  • the clinical trial is conducted to determine the safety and efficacy for treatment of the disease or disorder in the human patient population upon administration of the nauseogenic compound for a period of time from e.g., weeks to months to years.
  • clinical trials include at least one "treatment arm" of the human patient population to whom the nauseogenic compound is administered and at least one "placebo arm" to whom a placebo, rather than the nauseogenic compound, is administered.
  • Continuous dosing via delivery device, injectable dosing, and an oral dosing of the same nauseogenic compound generally differ in the amount of compound that is administered and need not be the same.
  • continuous dosing via delivery device may be e.g., 10 ⁇ g/day to 300 ⁇ g/day of a nauseogenic compound
  • injectable dosing may be e.g., 5 ⁇ g/injection to 300 ⁇ g/injection of the nauseogenic compound
  • oral dosing may be e.g. 10 mg/tablet to 3,000 mg/tablet of the nauseogenic compound.
  • the dose (e.g., continuous dosing via delivery device) is 10- 50 ⁇ g/day, 50-100 ⁇ g/day, 100-150 ⁇ g/day, or 150-300 ⁇ g/day.
  • the dose e.g., injectable dosing
  • the dose is 10-50 ⁇ g/injection, 50-100 ⁇ g/injection, 100-150 ⁇ g/injection, or 150-300 ⁇ g/inj ection.
  • the dose (e.g., oral dosing) is 10-50 mg/tablet, 50-500 mg/tablet, 500-1,000 mg/tablet, 1,000-3,000 mg/tablet.
  • All such doses and others, in any combination, are applicable to the disclosed methods despite potential differences in absolute amounts of nauseogenic compound that are dosed continuously and subcutaneously via delivery device, orally, or via injection. Rather, the disclosed methods relate to reductions in the incidence of nausea and/or vomiting that accompany a drug delivery device that subcutaneously administers an effective amount of the nauseogenic compound to the subject relative to incidence of nausea and/or vomiting that accompany injectable and oral administration of an effective amount of the nauseogenic compound, regardless of absolute or relative doses administered.
  • the second clinical trial relates to an administration of an injectable dose of the nauseogenic compound to a second human patient population. In some embodiments, the second clinical trial relates to an administration of an oral dose of the nauseogenic compound to a second human patient population. In some embodiments, the first clinical trial relates to continuous administration of the nauseogenic compound via delivery device to a human patient population.
  • incidence of nausea and/or vomiting is 25%, 24%, 23%,
  • the drug delivery device comprising a continuous dose of the nauseogenic compound to the first human patient population.
  • incidence of nausea and/or vomiting is ⁇ %-5%, 5%-10%, 10%-15%, 15%-20%, 20-25% or lower during the first clinical trial regarding administration of the drug delivery device comprising a continuous dose of the nauseogenic compound to the first human patient population.
  • incidence of nausea and/or vomiting is 99%, 90%, 80%, 70%, 60%, 50%, 40% 30%, 29%, 28%, 27%, 26%, 24%, 23%, 22%, 21 %, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1%, 10%, 9%, 8%, 7%, 6%, 5% or greater during the second clinical trial regarding administration of an injectable or oral dose of the nauseogenic compound to the second human patient population.
  • incidence of nausea and/or vomiting is 99%-75%, 75%- 50%, 50%-25%, 30-20%, 30-15%, 30-10%, 25-5% or greater during the second clinical trial regarding administration of an injectable or oral dose of the nauseogenic compound to the second human patient population.
  • a related method for treating a subject comprising contacting the subject with a drug delivery device comprising a nauseogenic compound and the drug delivery device administers the nauseogenic compound to the subject, wherein incidence of nausea and/or vomiting, reported as a percentage of a first human patient population, during a first clinical trial regarding administration of the drug delivery device comprising a continuous dose of the nauseogenic compound to the first human patient population, is reduced by at least 20% relative to incidence of nausea and/or vomiting, reported as a percentage of a second human patient population, during a second clinical trial regarding an administration of an injectable or an oral dose of the nauseogenic compound to the second human patient population.
  • a nauseogenic compound for use in a method of treating a subject, comprising contacting the subject with a drug delivery device comprising the nauseogenic compound and the drug delivery device administers the nauseogenic compound to the subject, wherein incidence of nausea and/or vomiting, reported as a percentage of a first human patient population, during a first clinical trial regarding administration of the drug delivery device comprising a continuous dose of the nauseogenic compound to the first human patient population, is reduced by at least 20% relative to incidence of nausea and/or vomiting, reported as a percentage of a second human patient population, during a second clinical trial regarding an administration of an injectable or an oral dose of the nauseogenic compound to the second human patient population.
  • Methods according to the fifth aspect relate to the percentage by which the incidence of nausea and/or vomiting is reduced by comparison of the lower incidence reported during the first clinical trial relative to the higher incidence reported during the second clinical trial.
  • incidence of nausea and/or vomiting of 5% reported as a percentage of a first human patient population, during a first clinical trial regarding administration of the drug delivery device comprising a continuous dose of the nauseogenic compound to the first human patient population is reduced by 50% relative to incidence of nausea and/or vomiting of 10%, reported as a percentage of a second human patient population, during a second clinical trial regarding an administration of an injectable or an oral dose of the nauseogenic compound to the second human patient population.
  • incidence of nausea and/or vomiting during a first clinical trial regarding administration of the drug delivery device comprising a continuous dose of the nauseogenic compound to the first human patient population is reduced by 20%-30%, 30%- 40%, 40%-50%, 50%-60%, 70%-80%, 80%-90%, 90%-100%, at least 25%, at least 50%, at least 75% relative to incidence of nausea and/or vomiting during a second clinical trial regarding an administration of an injectable or an oral dose of the nauseogenic compound to the second human patient population.
  • incidence of nausea and/or vomiting relates to the incidence reported by the human patient population who was administered the nauseogenic compound, and does not factor incidence of nausea and/or vomiting reported by a placebo group. In some embodiments, incidence of nausea and/or vomiting relates to the incidence reported by the human patient population who was administered the nauseogenic compound minus the incidence of nausea and/or vomiting reported by a placebo group.
  • Certain embodiments relate to an incidence of nausea. Other embodiments relate to an incidence of vomiting. Some embodiments relate to an incidence of nausea or vomiting. Some embodiments relate to an incidence of nausea and vomiting.
  • Certain embodiments relate to a prevalence of nausea. Other embodiments relate to a prevalence of vomiting. Some embodiments relate to a prevalence of nausea or vomiting. Some embodiments relate to a prevalence of nausea and vomiting.
  • the method is provided for treating diabetes in a subject. In some embodiments, the method is provided for treating type-2 diabetes in a subject.
  • the nauseogenic compound is a nauseogenic peptide. In some embodiments, the nauseogenic compound is a long-acting nauseogenic peptide.
  • the method for treating a subject for type-2 diabetes, comprising contacting the subject with an implantable osmotic drug delivery device comprising a long-acting nauseogenic peptide.
  • the long-acting nauseogenic peptide is selected from GLP-1 receptor agonist, PYY analog, amylin agonist, CGRP analog, or neurotensin analog.
  • the nauseogenic compound is a GLP-1 receptor agonist.
  • the long-acting GLP-1 receptor agonist is exenatide dispersed in a biocompatible polymer (Bydureon ® ), semaglutide (Ozempic ® ), liraglutide (Victoza ® ), albiglutide (Tanzeum ® ), or dulaglutide (Trulicity ® ).
  • the long-acting GLP-1 receptor agonist is semaglutide.
  • the long-acting GLP-1 receptor agonist is liraglutide.
  • the long-acting GLP-1 receptor agonist is albiglutide.
  • the long-acting GLP-1 receptor agonist is dulaglutide.
  • the long-acting GLP-1 receptor agonist is exenatide dispersed in a biocompatible polymer.
  • a related method for treating a subject comprising contacting the subject with a drug delivery device comprising a dose of a nauseogenic compound, wherein the drug delivery device administers the nauseogenic compound to the subject, during the first 24 hours following initiation of administration, less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject; and once Css is attained, Css of the nauseogenic compound is maintained in the plasma of the subject for at least two weeks.
  • Css mean steady state concentration
  • a nauseogenic compound for use in a method for treating a subj ect, comprising contacting the subject with a drug delivery device comprising a first dose of the nauseogenic compound, wherein the drug delivery device administers the nauseogenic compound to the subject, during the first 24 hours following initiation of administration, wherein less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject; and once Css is attained, Css of the nauseogenic compound is maintained in the plasma of the subject for at least two weeks.
  • Css mean steady state concentration
  • incidence e.g. , mean incidence during a period of time or during a clinical trial
  • a nauseogenic compound by the present methods, i.e. , by administration via drug delivery device, relative to incidence of nausea and/or vomiting from oral or injectable administration of the same nauseogenic compound.
  • Reduced incidence of nausea and/or vomiting may be established and compared against results of incidence of nausea and/or vomiting in pre-clinical studies, including animal models (e.g. , reduced appetite in rats or the onset of emesis in dogs) for nausea, vomiting, or reduced food intake.
  • incidence of nausea and/or vomiting from oral or injectable administration of a nauseogenic compound can be established, e.g. , from published clinical studies and/or information provided in the product insert of a marketed nauseogenic compound.
  • prevalence e.g. , statistical prevalence at a given point in time
  • a nauseogenic compound by the present methods, i.e. , by administration via drug delivery device, relative to prevalence of nausea and/or vomiting from oral or injectable administration of the same nauseogenic compound.
  • Prevalence of nausea and/or vomiting may be established and compared against results of pre-clinical studies, including animal models (e.g. , reduced appetite in rats or the onset of emesis in dogs) for nausea, vomiting, or reduced food intake.
  • prevalence of nausea and/or vomiting from oral or injectable administration of a nauseogenic compound can be established, e.g. , from published clinical studies and/or information provided in the product insert of a marketed nauseogenic compound.
  • the method for treating the subject includes a dose escalation, further comprising contacting the subject with an additional drug delivery device comprising a second dose of the nauseogenic compound, wherein the second dose is higher than the first dose.
  • the method for treating a subject does not include a dose escalation, comprising contacting the subject with an additional drug delivery device comprising the first dose of the nauseogenic compound.
  • the percentage of the human patient population who reported having nausea and/or vomiting, at the first and/or second dose, during the clinical trials is disclosed in published clinical studies and/or information provided in the product insert (i.e., prescribing information) of a marketed drug delivery device comprising the nauseogenic compound. In some embodiments, the percentage is a mean percentage.
  • the percentage of the human patient population who reported having nausea and/or vomiting, at the first and/or second dose, during the clinical trials was less than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%.
  • the percentage of the human patient population who reported having nausea and/or vomiting, at the first and/or second dose, during the clinical trials was 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%.
  • the percentage of human patient population reported as having nausea and/or vomiting at the first and/or second dose, during the clinical trials ranges from 0.01%-5%, 0.1%-5%, l%-5%, 0.01%-10%, 0.1%-10%, or 1%- 10%.
  • the number of patients in the human patient population in the clinical trials who are administered the drug delivery device comprising the first and/or second dose of a nauseogenic compound is from 20 to 1000. In some embodiments, the number of patients is from 20 to 200, 201 to 500, 501 to 1000, 1001 to 2000, 2001 to 3000, or 3001 to 4000.
  • patients in the human patient population were treated, on average, for 20 to 200 weeks, 20 to 100 weeks, 20 to 50 weeks, 51 to 100 weeks, or 101-200 weeks with drug delivery device comprising the first and/or second dose of a nauseogenic compound.
  • clinical trials include a placebo group of human patients who are not administered the drug delivery device comprising the first and/or second dose of the nauseogenic compound, and an active compound group of human patients who are administered the drug delivery device comprising the first and/or second dose of a nauseogenic compound.
  • both groups report having nausea and/or vomiting during the clinical trials, from the first and/or second dose of the nauseogenic compound, and the difference between the percentage of human patients in the active compound group who report having nausea and/or vomiting, and the percentage of human patients in the placebo group who report having nausea and/or vomiting, is less than 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%.
  • the percentage of human patients in the active compound group who report having nausea and/or vomiting, from the first and/or second dose of the nauseogenic compound is higher than the percentage of human patients in the placebo group who report having nausea and/or vomiting.
  • the percentage of human patients in the active compound group who report having nausea and/or vomiting, from the first and/or second dose of the nauseogenic compound is substantially similar to the percentage of human patients in the placebo group who report having nausea and/or vomiting.
  • the percentage of human patients who report having nausea and/or vomiting, from the first and/or second dose of the nauseogenic compound provided by the drug delivery device disclosed herein is less than the percentage of other human patients that reported having nausea and/or vomiting during previous clinical trials of an inj ectable form of the nauseogenic compound. In some embodiments, the percentage of human patients who reported having nausea and/or vomiting, from the first and/or second dose of the nauseogenic compound provided by the drug delivery device disclosed herein, was less than the percentage of other human patients that reported having nausea and/or vomiting during previous clinical trials of an orally available form of the nauseogenic compound.
  • Certain embodiments relate to human patients that reported having nausea from the nauseogenic compound. Other embodiments relate to human patients that reported vomiting from the nauseogenic compound. Other embodiments relate to human patients that reported nausea or vomiting from the nauseogenic compound. Other embodiments relate to human patients that reported nausea and vomiting from the nauseogenic compound.
  • the nauseogenic compound is semaglutide. In certain embodiments, the nauseogenic compound is liraglutide. In certain embodiments, the nauseogenic compound is dulaglutide.
  • the nauseogenic compound is semaglutide and the method is provided for treating type-2 diabetes in the subject. In certain embodiments, the nauseogenic compound is liraglutide and the method is provided for treating type-2 diabetes in the subject. In certain embodiments, the nauseogenic compound is dulaglutide and the method is provided for treating type-2 diabetes in the subject.
  • a method for treating type-2 diabetes in the subject comprising contacting the subject with a drug delivery device comprising a first dose of semaglutide the drug delivery device administers the semaglutide to the subject, and contacting occurs after an administration of the drug delivery device comprising semaglutide to a human patient population during clinical trials; where less than 15% of the human patient population, to whom the drug delivery device comprising the first dose of semaglutide was administered, reported having nausea during the clinical trials.
  • a method for treating type-2 diabetes in the subject comprising contacting the subject with a drug delivery device comprising a first dose of liraglutide, wherein the drug delivery device administers the liraglutide to the subject, and the contacting occurs after an administration of the drug delivery device comprising semaglutide to a human patient population during clinical trials; where less than 15% of the human patient population, to whom the drug delivery device comprising the first dose of liraglutide was administered, reported having nausea during the clinical trials. .
  • a method for treating type-2 diabetes in the subject comprising contacting the subject with a drug delivery device comprising a first dose of dulaglutide, wherein the drug delivery device administers the dulaglutide to the subject, and the contacting occurs after an administration of the drug delivery device comprising dulaglutide to a human patient population during clinical trials; where less than 15% of the human patient population, to whom the drug delivery device comprising the first dose of dulaglutide was administered, reported having nausea during the clinical trials.
  • the nauseogenic compound is a nauseogenic peptide selected from the group consisting of adrenomedullin, amylin, angiotensin II, atrial natriuretic peptide, cholecystokinin, chorionic gonadotropin leuteinizing hormone, corticotrophin releasing factor, endothelins, gastrin, ghrelin, glucagon, glucagon-like peptide 1 (GLP-1), insulin, insulin-like growth factor, leptin, leu-enkephalin, melanocortins, neurotensin, oxytocin, parathyroid hormones (e.g., PTH, PTHrP), pituitary adenylate cyclase activating peptide (PACAP), prolactin, prolactin releasing peptide, somatostatin, tachykinins (e.g., substance PTH, PTHrP), pit
  • the method is provided for treatment of type-2 diabetes in the subject. In some embodiments, the method is provided for providing glycemic control in the subject. In some embodiments, the method is provided for treatment (including e.g., prevention, inhibition, suppression, delaying the progression) of a "variety of conditions" in the subject, wherein "variety of conditions," as used herein, includes but is not limited to the following: chronic pain, hemophilia and other blood disorders, endocrine disorders, metabolic disorders, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Alzheimer's disease, cardiovascular diseases (e.g.
  • diabetes including type 1, type 2 diabetes mellitus, human immunodeficiency virus treatment-induced, latent autoimmune diabetes in adults, and steroid-induced
  • obesity hypoglycemia unawareness, restrictive lung disease, chronic obstructive pulmonary disease, lipoatrophy, metabolic syndrome, leukemia, hepatitis, renal failure, infectious diseases (including bacterial infection, viral infection (e.g., infection by human immunodeficiency virus, hepatitis C virus, hepatitis B virus, yellow fever virus, West Nile virus, Dengue virus, Marburg virus, and Ebola virus), and parasitic infection), hereditary diseases (such as cerebrosidase deficiency and adenosine deaminase deficiency), hypertension, septic shock, autoimmune diseases (e.g., Grave's disease, systemic lupus erythematosus, multiple sclerosis,
  • some of the above agents are useful for the treatment of infectious diseases requiring chronic treatments including, but not limited to, tuberculosis, malaria, leishmaniasis, trypanosomiasis (sleeping sickness and Chagas disease), and parasitic worms.
  • the method for treatment of the subject corresponds to the method for treatment of the human patient population during clinical trials.
  • the subject of the method and the human patient population of the clinical trials are treated for the same condition.
  • the drug delivery device administers the nauseogenic compound to the subject, during the first 24 hours following initiation of administration, wherein less than or equal to 90% of mean steady state concentration (C ss ) of the nauseogenic compound is attained in the plasma of the subject; and once C ss is attained, C ss of the nauseogenic compound is maintained in the plasma of the subject for at least two weeks.
  • C ss mean steady state concentration
  • the incidence of nausea and/or vomiting is less than 75%, 50%, 25%, 20%, 10%, 5%, 2% or 1% relative to incidence of nausea from oral or injectable administration of the same nauseogenic compound. In some embodiments, during treatment of a patient with a nauseogenic compound by the present methods, the incidence of nausea and/or vomiting is substantially eliminated.
  • Css of the nauseogenic compound is gradually attained in plasma.
  • 90% of mean steady state concentration (Css) in plasma of the nauseogenic compound is not reached in the subject until 1 week to 8 weeks following administration.
  • 90% of mean steady state concentration (Css) in plasma of the nauseogenic compound is not reached in the subject until 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or between any two of these time periods, following administration.
  • Css mean steady state concentration
  • an initial concentration (Ci) in plasma of the nauseogenic compound, following initiation of administration, is lower than subsequent Css, gradually attained.
  • a maximum steady state concentration Cmax of nauseogenic compound does not substantially exceed the mean steady state concentration (Css) of the nauseogenic compound.
  • initial concentration (Ci) in plasma of the nauseogenic compound, during the first 12 hours following initiation of administration is less than or equal to 50%, 25 % or 10% of mean steady state concentration (Css) in plasma of the nauseogenic compound that will be attained in the subject.
  • initial concentration (Ci) in plasma of the nauseogenic compound, during the first 24 hours following initiation of administration is less than or equal to 50%, 25 % or 10% of mean steady state concentration (Css) in plasma of the nauseogenic compound that will be attained in the subject.
  • initial concentration (Ci) in plasma of the nauseogenic compound, during the first 2 days, 3 days, 4 days, 5 days, 6 days or 7 days following initiation of administration is less than or equal to 50%, 25 % or 10% of mean steady state concentration (Css) in plasma of the nauseogenic compound that will be attained in the subject.
  • peak-trough fluctuations in plasma concentration of the nauseogenic compound have been found to exacerbate the incidence and/or prevalence of nausea and vomiting.
  • Css of the nauseogenic compound is attained in the plasma of the subject without incurring substantial peak-trough fluctuations in plasma concentration of the nauseogenic compound.
  • a "substantial peak-trough fluctuation" includes fluctuations of at least 1%, 2%, 3%, 4%, 5%, 10%, 20% or 30% relative to Css of the nauseogenic compound.
  • Css, once attained is steadily maintained in plasma of the patient for at least 2 weeks. In some embodiments, Css, once attained is steadily maintained in plasma of the patient for 2-6 weeks, 6-10 weeks, 10-14 weeks, or 14-18 weeks. In some additional embodiments, Css, once attained is steadily maintained in plasma of the patient for weeks, months, one year or longer. In some embodiments, Css, once attained is steadily maintained for one month, two months, three months, four months, five months, six months, nine months, one year, eighteen months, two years or three years. In some embodiments, Css is maintained if mean Css does not spike or fall within 30%, 20%, 10%, 5%, 2% or 1% during a given period of time.
  • nausea and vomiting can be curtailed when rate of change, particularly positive rate of change, in plasma concentration of the nauseogenic compound is minimized during treatment.
  • nausea and/or vomiting can be curtailed when rate of change in plasma concentration, described herein as dfnauseogenic compoundj/dt, is held to less than about +5%, +4%, +3%, or +2% per hour relative to the mean steady state concentration (Css) of the nauseogenic compound.
  • Css mean steady state concentration
  • mean Css is gradually attained based on a rate of change in plasma concentration less than about +5%, +4%, +3%, or +2% per hour. This implies a slow and steady ramp up in concentration of the nauseogenic compound to mean Css without substantial fluctuations/changes in concentration over time.
  • dfnauseogenic compoundj/dt is less than +1% of the mean Css of the nauseogenic compound per hour. In some embodiments, dfnauseogenic compoundj/dt is less than +0.5% of the mean steady state concentration (Css) of the nauseogenic compound per hour. In some embodiments, dfnauseogenic compoundj/dt is less than +0.25% of the mean steady state concentration (Css) of the nauseogenic compound per hour.
  • dfnauseogenic compoundj/dt is less than +5%, +4%, +3%, +2%, +1%, +0.5% or +0.25% of the mean Css of the nauseogenic compound per hour and (ii) less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject during the first 36 hours, 48 hours, 60 hours, 72 hours, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or between any two of these time periods, following administration.
  • dfnauseogenic compoundj/dt is less than +4% of the mean steady state concentration (Css) of the nauseogenic compound per hour; and less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject during the first 7 days following administration.
  • dfnauseogenic compoundj/dt is less than +1% of the mean Css of the nauseogenic compound per hour and (ii) less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject during the first 36 hours, 48 hours, 60 hours, 72 hours, 4 days, 5 days, 6 days, 7 days,
  • dfnauseogenic compound] /dt is less than +1% of the mean ss of the nauseogenic compound per hour and (ii) less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject during the first 14 days following administration.
  • dfnauseogenic compoundj/dt is less than +1% of the mean Css of the nauseogenic compound per hour and (ii) less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject during the first 6 weeks following administration.
  • (i) dfnauseogenic compound] /dt is less than +1% of the mean Css of the nauseogenic compound per hour and (ii) less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject during the first 8 weeks following administration.
  • dfnauseogenic compoundj/dt is less than +0.5% of the mean Css of the nauseogenic compound per hour and (ii) less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject during the first 36 hours, 48 hours, 60 hours, 72 hours, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or between any two of these time periods, following administration.
  • dfnauseogenic compoundj/dt is less than +0.5% of the mean Css of the nauseogenic compound per hour and (ii) less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject during the first 14 days following administration. In some embodiments, (i) dfnauseogenic compoundj/dt is less than +0.5% of the mean Css of the nauseogenic compound per hour and (ii) less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject during the first 6 weeks following administration.
  • dfnauseogenic compoundj/dt is less than +0.5% of the mean Css of the nauseogenic compound per hour and (ii) less than or equal to 90% of mean steady state concentration (Css) of the nauseogenic compound is attained in the plasma of the subject during the first 8 weeks following administration.
  • nauseogenic compounds having an extended elimination half-life (tin) in humans are particularly suitable to the present methods of administration via drug delivery devices.
  • the nauseogenic compound is a long-acting nauseogenic peptide.
  • the nauseogenic compound has a ti/ 2 in humans of at least about 1 day, 2 days or 5 days.
  • the nauseogenic compound has a ti/2 in humans of about 1 day to 14 days.
  • the nauseogenic compound has a ti/2 in humans of about 6 days to 14 days.
  • the nauseogenic compound has a tin in humans of about 7 days to 9 days.
  • HSA human serum albumin
  • the long-acting nauseogenic peptide such as an acylated long-acting peptide or acylated long-acting GLP-1 analogue, can simultaneously bind to albumin and its intended receptor, such as the GLP-1 receptor.
  • the long-acting nauseogenic peptide is an acylated long-acting GLP-1 receptor agonist that bind to the GLP-1 receptor with an affinity below 100 nM, preferable below 30 nM in the presence of 2% albumin.
  • the long-acting nauseogenic peptide is an acylated long- acting peptide or acylated long-acting GLP-1 receptor agonist that binds human serum albumin (HSA) and exhibits an albumin-mediated potency decrease (e.g., 10-200 fold, 10-100 fold, 10- 50 fold, 10-30 fold, or 10-25 fold) in activation of GLP-1 receptors at 4% HSA versus its potency for activation of GLP-1 receptors at 0.1% HSA.
  • HSA human serum albumin
  • albumin-mediated potency decrease e.g., 10-200 fold, 10-100 fold, 10- 50 fold, 10-30 fold, or 10-25 fold
  • semaglutide exhibits a 19.9x albumin-mediated decrease in potency for activation of GLP-1 receptors at 4% HSA versus its potency for activation of GLP-1 receptors at 0.1% HSA.
  • the nauseogenic compound is a long-acting nauseogenic peptide having a binding affinity to its intended receptor that is decreased 20-50 fold in the presence of 4% human serum albumin when comparing the binding affinity in the presence of very low concentration 0.1% of human serum albumin.
  • the long-acting nauseogenic peptide is an acylated long- acting peptide or acylated long-acting GLP-1 receptor agonist that binds HSA and exhibits a reduction in potency for activation of its intended receptor, such as the GLP-1 receptor in the presence of physiologic concentrations (2-4%) HSA versus the potency observed with low (0.1%) HSA concentrations.
  • GLP-1 [7-36]NH2 exhibits no substantial reduction, or a slight increase, in potency for activation of GLP-1 receptors in the presence of physiologic concentrations (2-4%) HSA versus the potency observed with low (0.1%) HAS concentrations.
  • the long-acting nauseogenic peptide is an acylated long- acting peptide or acylated long-acting GLP-1 receptor agonist that binds human serum albumin (HSA) and exhibits an albumin-mediated potency shift (e.g., 20-200 fold, 20-100 fold, 20-50 fold, 30-50 fold, or 30-40 fold) relative to any potency shift (e.g., increase or decrease) for human GLP-1 [7-36]NH2.
  • HSA human serum albumin
  • GLP-1 [7-36]NH2 exhibits an albumin-mediated 0.54x increase in potency for activation of GLP-1 receptors at 4% HSA versus potency for activation of GLP-1 receptors at 0.1% HSA whereas semaglutide exhibits an albumin-mediated 19.9x decrease in potency for activation of GLP-1 receptors at 4% HSA versus potency for activation of GLP-1 receptors at 0.1% HSA. Semaglutide thus exhibits, in the assay conditions of Example 2, an albumin-mediated potency shift of 36.8-fold (19.9/0.54) relative to potency shift for human GLP-1 [7-36]NH2.
  • the nauseogenic compound is an acylated long-acting GLP-1 receptor agonist that binds human serum albumin (HSA) and exhibits an albumin- mediated potency decrease 10-25 fold in the presence of 4% human serum albumin relative its potency in the presence of very low concentration 0.1% of human serum albumin.
  • HSA human serum albumin
  • albumin binding moiety means a residue (e.g., aliphatic substituents or acylated group comprising an aliphatic substituent) which permits the long- acting nauseogenic peptide to bind non-covalently to human serum albumin.
  • the long-acting nauseogenic peptide having an attached albumin binding residue typically has an affinity below 10 ⁇ to human serum albumin and preferably below 1 ⁇ .
  • a range of albumin binding residues, having aliphatic substituents are known including linear and branched lipophilic moieties, described herein, comprising 4-40 carbon atoms.
  • the long-acting nauseogenic peptide has an apparent KD for association with albumin not greater than 1 micromole/liter. In some embodiments, the long- acting nauseogenic peptide has an off rate for dissociation of the long-acting nauseogenic peptide from albumin not greater than 0.002/sec. In other words, not more than 0.2% of peptide-albumin complex will dissociate in a drug-free environment in 1 second.
  • the long-acting nauseogenic peptide comprises a lipophilic substituent, as described in greater detail below. In some embodiments, the long-acting nauseogenic peptide comprises any one of the lipophilic substituents described in greater detail herein.
  • the drug delivery device is an implantable drug delivery device. In some embodiments, the device is an implantable osmotic delivery device.
  • the implantable drug delivery device administers a continuous dose of the nauseogenic compound.
  • treatment consists of a single dose of the nauseogenic compound.
  • treatment consists of a relatively low initial dose of the nauseogenic compound followed by a higher maintenance dose of the nauseogenic compound.
  • Semaglutide for example, is administered at a relatively low initial dose of 0.5 mg/week (corresponding to about 71 ⁇ g/day) followed by a higher maintenance dose of 1.0 mg/week (corresponding to about 143 ⁇ g/day).
  • the nauseogenic compound is continuously administered at a dose ⁇ g/day) less than, equal to or greater than an FDA-approved maintenance dose ⁇ g/day or mg/week) of the nauseogenic compound administered via bolus injection. In some embodiments, the nauseogenic compound is continuously administered at a dose ⁇ g/day) less than, equal to or greater than an FDA- approved initial dose ⁇ g/day or mg/week) of the nauseogenic compound administered via bolus injection. In some embodiments, the nauseogenic compound is a long-acting nauseogenic peptide. In some embodiments, the long-acting nauseogenic peptide is a long- acting GLP-1 agonist such as semaglutide. In some embodiments, the long-acting nauseogenic peptide is a long-acting GLP-1 agonist such as liraglutide.
  • the implantable drug delivery device administers a continuous dose of about 1 mg/day, 500 ⁇ g/day, 250 ⁇ g/day, 150 ⁇ g/day, 143 ⁇ g/day, 140 ⁇ g/day, 130 ⁇ g/day, 120 ⁇ g/day, 110 ⁇ g/day, 100 ⁇ g/day, 90 ⁇ g/day, 80 ⁇ g/day, 70 ⁇ g/day, 60 ⁇ g/day, 50 ⁇ g/day, 40 ⁇ g/day, 30 ⁇ g/day, 20 ⁇ g/day, 10 ⁇ g/day, or a continuous dose between any two of these values, of the nauseogenic compound.
  • the implantable drug delivery device administers a continuous dose of about 1-10 ⁇ g/day, 10-20 ⁇ g/day, 20-30 ⁇ g/day, 30-40 ⁇ g/day, 40-50 ⁇ g/day, 50-60 ⁇ g/day, 60-70 ⁇ g/day, 70-80 ⁇ g/day, 90-100 ⁇ g/day, 100-110 ⁇ g/day, 110-120 ⁇ g/day, 120-130 ⁇ g/day, 130-140 ⁇ g/day, 140-150 ⁇ g/day, 150-200 ⁇ g/day, 200-250 ⁇ g/day, 250-500 ⁇ g/day, or 500-1,000 ⁇ g/day.
  • the device is a non-implantable delivery device.
  • the device is a non-implantable miniaturized patch pump, e.g., JewelPUMPTM (Debiotech S.A.), placed on the surface of the skin.
  • dosing of the non- implantable miniaturized patch pump is adjustable and programmable. As such, mean steady state concentration (Css) in plasma of a short-acting or long-acting nauseogenic compound can gradually be attained, via slow ramp-up of an increasing dosage, in the subject over days, weeks or months.
  • the non-implantable miniaturized patch pump is remotely controlled.
  • the non-implantable miniaturized patch pump administers a non-continuous dose of the nauseogenic compound. In some embodiments, the non- implantable miniaturized patch pump administers an increasing dose of the nauseogenic compound.
  • the non-implantable miniaturized patch pump administers a short-acting nauseogenic peptide. In some embodiments, the non-implantable miniaturized patch pump administers a long-acting nauseogenic peptide.
  • a method for treating any condition or disease in a subject, wherein treatment nausea and/or vomiting are side effects of treatment.
  • a method is provided for treating diabetes in a subject.
  • a method is provided for treating type-2 diabetes in a subject.
  • a method is provided for treating obesity in a subject.
  • a method is provided for effecting weight loss in a subject.
  • a method is provided for treating cancer in a subject, e.g. , by administration of nauseogenic compounds such as chemotherapy.
  • a method is provided for controlling pain in a subject, e.g. , by administration of nauseogenic compounds such as opiates.
  • the drug delivery device comprises a solid suspension of the nauseogenic compound. In some embodiments, the drug delivery device comprises a substantially anhydrous formulation of the nauseogenic compound.
  • Nauseogenic compounds including nauseogenic peptides, have been developed for the treatment of a variety of diseases and disorders.
  • nauseogenic peptides for the treatment of diabetes include type-2 diabetes (T2D)
  • T2D type-2 diabetes
  • nauseogenic peptides for the treatment of diabetes include glucagon-like peptide- 1 (GLP-1) agonists, peptide YY (also known as PYY, peptide tyrosine tyrosine or pancreatic peptide YY3-36) analogs, and amylin analogs (e.g. , pramlintide, developed by Amylin Pharmaceuticals, marketed by AstraZeneca).
  • GLP-1 agonists, PYY analogs and amylin analogs are administered subcutaneously via periodic self-injections that generally induce nausea in patients.
  • Such peptides are generally classified as shorter-acting or longer-acting peptides based on their pharmacokinetic (PK) profiles following subcutaneous administration.
  • PK pharmacokinetic
  • GLP-1 agonists such as exenatide and lixisenatide (Adlyxin ® )
  • longer-acting GLP-1 receptor agonists such as liraglutide (Victoza ® ) and semaglutide, have half-lives in human serum of approximately 16 and 165 hours, respectively, following subcutaneous administration.
  • the nauseogenic compound is a nauseogenic peptide selected from GLP-1 receptor agonist, amylin analog, PYY analog (including any of those disclosed in U.S. Patent Application Publication No. : 2014/0329742; said PYY analogs are incorporated herein by reference), amylin agonist, calcitonin gene-related peptide (CGRP) analog, or neurotensin analog.
  • the nauseogenic compound is a long-acting nauseogenic peptide selected from GLP-1 receptor agonist, amylin analog, PYY analog, amylin agonist, CGRP analog, or neurotensin analog, each of which comprises a lipophilic group, optionally bound to the peptide via a spacer.
  • the nauseogenic compound is a GLP-1 receptor agonist. In some embodiments, the nauseogenic compound is a short-acting GLP-1 receptor agonist. In some embodiments, the nauseogenic compound is a long-acting GLP-1 receptor agonist. In some embodiments, the nauseogenic compound is a GLP-1 receptor agonist co-formulated with insulin. In some embodiments, the nauseogenic compound is a GLP-1 receptor agonist co-formulated with an insulin analog or functional variant.
  • a “functional variant” means a portion of the native protein that preserves the full activity of the native parent protein. In some embodiments, the portion of the native protein preserves partial activity of the native parent protein. In some embodiments, the portion may be part of a complex (protein, carbohydrate, or other). In other embodiments a functional variant is equivalent in meaning to an "analog.”
  • Insulin analogs such as those that may be coformulated with a GLP-1 receptor agonist, include ultra-fast rapid-acting insulins (e.g., Novo Nordisk's Fiasp®), rapid-acting insulins (e.g., Lilly's Humalog®, Novo Nordisk's Novolog®, Sanofi's Apidra® or Admelog®), short-acting insulins (e.g., Novo Nordisk's Novolin®) and particularly the long-acting insulins (e.g., insulin detemir, Novo Nordisk's Levemir®; insulin degludec, Novo Nordisk's Tresiba®; or insulin glargine, including Lilly's Basaglar®, Sanofi's Lantus® or Sanofi's Toujeo®).
  • the GLP-1 receptor agonist is coformulated with an insulin analog that is a long- acting insulin (e.g., insulin detemir, insulin
  • Short-acting GLP-1 receptor agonists are GLP-1 receptor agonists having a mean terminal half-life in humans of less than 5 hours following subcutaneous administration.
  • Exenatide (AstraZeneca; Byetta ® ): In some embodiments, the short-acting GLP-1 receptor agonist is exenatide.
  • Byetta ® was the first approved GLP-1 receptor agonist (in 2005) as antidiabetic therapy for the treatment of T2D. It has a terminal half-life of approximately 2.4 h after subcutaneous administration and is applied twice daily (5 ⁇ g & 10 ⁇ g per injection).
  • Exenatide has the following amino acid sequence: H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Glu-Ala- Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro- Pro-Ser-NH 2 (SEQ ID NO: 1)
  • Lixisenatide (Sanofi; Adlyxin ® )
  • the short-acting GLP-1 receptor agonist is lixisenatide, a synthetic analog of exenatide, developed by Zealand Pharma A/S and marketed by Sanofi.
  • Relative to exenatide six lysine residues have been added to the C-terminus, which is also amidated, and having one deleted proline residue at the C-terminal region.
  • Long-acting GLP-1 receptor agonists are GLP-1 receptor agonists having a mean terminal half-life in humans of at least 5 hours following subcutaneous administration.
  • the long-acting GLP-1 receptor agonist has a mean terminal half-life in humans of at least 8, 10, 12, 16, 20, 24 hours, or 2, 3 4, 5, 6, 7 8, 9, 10 or more days following subcutaneous administration.
  • the long-acting GLP-1 receptor agonist is exenatide dispersed in a biocompatible polymer (Bydureon ® ), semaglutide (Ozempic ® ), liraglutide (Victoza ® ), albiglutide (Tanzeum ® ), or dulaglutide (Trulicity ® ).
  • GLP-1 receptor agonists are attained, at least in part, by (i) slow release of a GLP-1 receptor agonist from polymeric matrices e.g. , exenatide extended release Bydureon ® (AstraZeneca); (ii) conjugation of a lipophilic substituent to the GLP-1 receptor agonist, e.g. , acylated GLP-1 receptor agonists, liraglutide Victoza ® ; and semaglutide Ozempic ® ; (both from Novo Nordisk); (iii) conjugation of the GLP-1 receptor agonist to albumin, e.g.
  • Extended release exenatide Bydureon ® (developed by Amylin and marketed by AstraZeneca) is a once-weekly formulation of exenatide, in which exenatide is noncovalently sequestered within a biodegradable polymeric matrix microspheres consisting of poly(D,L- lactide-co-glycolide) (PLG). Slow release from the polymeric matrix takes place through diffusion and microsphere breakdown.
  • Exenatide formulated as Bydureon ® for extended release, has the same amino acid sequence (SEQ ID NO: l) as the exenatide of Byetta ® .
  • the long-acting GLP-1 receptor agonist is exenatide dispersed in a biocompatible polymer.
  • the long-acting GLP-1 receptor agonist is a pharmaceutical composition comprising exenatide in a biocompatible poly(lactide-co-glycolide) copolymer, as described in U.S. Patent No. : 8,329,648.
  • the long-acting GLP-1 receptor agonist is a composition provided for sustained-release of exenatide, consisting essentially of: a biocompatible polymer having dispersed therein about 3%-5% (w/w) exenatide and about 2% (w/w) sucrose, as described in U.S. Patent No. : 7,456,254.
  • the long-acting GLP-1 receptor agonist is a composition that consists of: a biocompatible polymer having dispersed therein about 5% (w/w) exenatide and about 2% (w/w) sucrose.
  • the biocompatible polymer is selected from poly(lactides), poly(glycolides), poly(lactide-co- glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s and blends and copolymers thereof.
  • the biocompatible polymer is poly(lactide-co-glycolide) with a lactide:glycolide ratio of about 1 : 1.
  • Conjugation of one or more "lipophilic substituents" to long-acting nauseogenic peptides, including long-acting GLP-1 receptor agonists, is intended to prolong the action of the long-acting peptide by facilitating binding to serum albumin and delayed renal clearance of the conjugated peptide.
  • a "lipophilic substituent” comprises a substituent comprising 4-40 carbon atoms, in particular 8-25 carbon atoms, or 12 to 22 carbon atoms.
  • the lipophilic substituent may be attached to an amino group of the long-acting nauseogenic peptide or long-acting GLP-1 receptor agonist by means of a carboxyl group of the lipophilic substituent which forms an amide bond with an amino group of the amino acid residue to which it is attached.
  • the long-acting nauseogenic peptide or long-acting GLP-1 receptor agonists include three, two, or preferably one lipophilic substituent.
  • the long-acting nauseogenic peptide or long-acting GLP-1 agonist has only one lipophilic substituent which substituent comprises an alkyl group or a group which has an co-carboxylic acid group and is attached to the N-terminal amino acid residue of the parent peptide.
  • the long-acting nauseogenic peptide or long-acting GLP-1 receptor agonist has only one lipophilic substituent which substituent is an alkyl group or a group which has an co-carboxylic acid group and is attached to the C-terminal amino acid residue of the parent peptide.
  • the long-acting nauseogenic peptide or long-acting GLP-1 derivative has only one lipophilic substituent which substituent can be attached to any one amino acid residue which is not the N-terminal or C-terminal amino acid residue of the parent peptide.
  • the long-acting nauseogenic peptide or long-acting GLP-1 receptor agonist includes two three or four lipophilic substituents.
  • the lipophilic substituent has a group which can be negatively charged.
  • One preferred such group is a carboxylic acid group.
  • the lipophilic substituent is a straight-chain or branched alkyl group.
  • the lipophilic substituent is the acyl group of a straight-chain or branched fatty acid.
  • the lipophilic substituent is an acyl group of the formula CH3(CH2)nCO— , wherein n is an integer from 4 to 38, preferably an integer from 4 to 24, more preferably CH 3 (CH 2 )6CO— , CH 3 (CH 2 )8CO— , CH 3 (CH 2 )ioCO— , CH 3 (CH 2 )i2CO— , CH 3 (CH 2 )i4CO— , CH 3 (CH 2 )ieCO— , CH 3 (CH 2 )isCO— , CH 3 (CH 2 ) 2 oCO— or CH 3 (CH 2 ) 22 CO— .
  • the lipophilic substituent is an acyl group of a straight-chain or branched alkane ⁇ , ⁇ -dicarboxylic acid.
  • the lipophilic substituent is an acyl group of the formula HOOC(CH 2 )mCO— , wherein m is an integer from 4 to 38, preferably an integer from 4 to 24, more preferably HOOC(CH 2 )i 4 CO— , HOOC(CH 2 )ieCO— , HOOC(CH 2 )isCO— , HOOC(CH 2 ) 20 CO— or HOOC(CH 2 ) 22 CO— .
  • the lipophilic substituent is attached, optionally via a spacer, to the ⁇ -amino group of a Lys residue contained in the parent peptide of the long-acting nauseogenic peptide or long-acting GLP-1 derivative.
  • the lipophilic substituent is attached to the parent peptide of the long-acting nauseogenic peptide or long-acting GLP-1 receptor agonist by means of a "spacer" which is an unbranched alkane ⁇ , ⁇ -dicarboxylic acid group having from 1 to 7 methylene groups, preferably two methylene groups which spacer forms a bridge between an amino group of the parent peptide and an amino group of the lipophilic substituent.
  • a "spacer" which is an unbranched alkane ⁇ , ⁇ -dicarboxylic acid group having from 1 to 7 methylene groups, preferably two methylene groups which spacer forms a bridge between an amino group of the parent peptide and an amino group of the lipophilic substituent.
  • the spacer is an amino acid, for example, succinic acid, Lys, Glu or Asp, or a dipeptide such as Gly-Lys.
  • the spacer is succinic acid
  • one carboxyl group thereof may form an amide bond with an amino group of the amino acid residue
  • the other carboxyl group thereof may form an amide bond with an amino group of the lipophilic substituent.
  • the spacer when the spacer is Lys, Glu or Asp, the carboxyl group thereof may form an amide bond with an amino group of the amino acid residue, and the amino group thereof may form an amide bond with a carboxyl group of the lipophilic substituent.
  • a further spacer may in some instances be inserted between the ⁇ -amino group of Lys and the lipophilic substituent.
  • a further spacer is succinic acid which forms an amide bond with the ⁇ -amino group of Lys and with an amino group present in the lipophilic substituent.
  • such a further spacer is Glu or Asp which forms an amide bond with the ⁇ -amino group of Lys and another amide bond with a carboxyl group present in the lipophilic substituent, that is, the lipophilic substituent is a ⁇ -acylated lysine residue.
  • the lipophilic substituent has a group which can be negatively charged, for example, a carboxylic acid group or other compound that has a carboxyl group.
  • Representative long-acting GLP-1 agonists comprising a single lipophilic substituent include liraglutide and semaglutide.
  • Liraglutide (Victoza ® , developed and marketed by Novo Nordisk) is administered via daily injection for treatment of type-2 diabetes. Liraglutide has 97% sequence identity to GLP-l(7-37). Liraglutide is modified by two amino acid changes (one addition and one substitution) and by the addition of a lipophilic substituent that enables it to form a noncovalent bond with serum albumin following subcutaneous administration.
  • the long-acting GLP-1 receptor agonist is liraglutide, i.e., Lys 26 (N e -(Y-glutamyl(N a - hexadecanoyl))), Arg 4 -GLP-l(7-37), which has the following structural Formula I (SEQ ID NO:3):
  • the long-acting GLP-1 receptor agonist is liraglutide that is co-formulated with insulin or an insulin analog.
  • a long- acting GLP-1 receptor agonist of Formula II SEQ ID NO:4, as described in U.S. Patent No.: 7,235,627:
  • Xaa at position 7 is His, a modified amino acid, or is deleted
  • Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, He, Val, Glu, or Asp,
  • Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, He, Val, Glu, Asp, or Lys,
  • Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, or Lys,
  • Xaa at position 20 is Leu, Ala, Gly, Ser, Thr, Leu, He, Val, Glu, Asp, or Lys,
  • Xaa at position 21 is Glu, Asp, or Lys
  • Xaa at position 22 is Gly, Ala, Ser, Thr, Leu, He, Val, Glu, Asp, or Lys
  • Xaa at position 23 is Gin, Asn, Arg, Glu, Asp, or Lys
  • Xaa at position 24 is Ala, Gly, Ser, Thr, Leu, He, Val, Arg, Glu, Asp, or Lys,
  • Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, He, Val, Glu, Asp, or Lys,
  • Xaa at position 26 is Lys, Arg, Gin, Glu, Asp, or His,
  • Xaa at position 27 is Glu, Asp, or Lys
  • Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, He, Val, Glu, Asp, or Lys,
  • Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys,
  • Xaa at position 32 is Leu, Gly, Ala, Ser, Thr, He, Val, Glu, Asp, or Lys,
  • Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Leu, He, Glu, Asp, or Lys,
  • Xaa at position 34 is Lys, Arg, Glu, Asp, or His,
  • Xaa at position 35 is Gly, Ala, Ser, Thr, Leu, He, Val, Glu, Asp, or Lys,
  • Xaa at position 36 is Arg, Lys, Glu, Asp, or His,
  • Xaa at position 37 is Gly, Ala, Ser, Thr, Leu, He, Val, Glu, Asp, or Lys or is deleted
  • Xaa at position 38 is Arg, Lys, Glu, Asp, or His, or is deleted,
  • Xaa at position 39 is Arg or is deleted, or
  • the long-acting GLP-1 receptor agonist contains only one Lys and the Lys is not the N-terminal or C-terminal amino acid of the derivative
  • a lipophilic substituent of from 12 to 25 carbons is attached, optionally via a spacer, to the ⁇ -amino group of the Lys, and
  • the total number of different amino acids between the long-acting GLP-1 receptor agonist and the corresponding native form of GLP- 1 does not exceed five.
  • Xaa at position 7 is His
  • Xaa at position 8 is Ala
  • Xaa at position 26 is Arg, Gin, Glu, Asp, or His, and the total number of different amino acids between the long-acting GLP-1 receptor agonist and the corresponding native form of GLP-1 does not exceed three.
  • Xaa at position 34 is Lys
  • Xaa at position 37 is Gly or is deleted
  • Xaa at position 38 is Arg or is deleted
  • Xaa at position 39 is deleted.
  • the total number of different amino acids between the long-acting GLP-1 receptor agonist and the corresponding native form of GLP-1 does not exceed two.
  • the total number of different amino acids between the long-acting GLP-1 receptor agonist and the corresponding native form of GLP-1 is one.
  • Xaa at position 34 is Arg, Glu, Asp, or His.
  • Xaa at position 18 is Lys
  • Xaa at position 37 is Gly or is deleted
  • Xaa at position 38 is Arg or is deleted
  • Xaa at position 39 is deleted and each of the other Xaa is the amino acid in the native form of GLP-1 (7-36), (7-37) or (7- 38).
  • Xaa at position 23 is Lys
  • Xaa at position 37 is Gly or is deleted
  • Xaa at position 38 is Arg or is deleted
  • Xaa at position 39 is deleted and each of the other Xaa is the amino acid in the native form of GLP-1 (7-36), (7-37) or (7- 38).
  • Xaa at position 27 is Lys
  • Xaa at position 37 is Gly or is deleted
  • Xaa at position 38 is Arg or is deleted
  • Xaa at position 39 is deleted and each of the other Xaa is the amino acid in the native form of GLP-1 (7-36), (7-37) or (7- 38).
  • Xaa at position 36 is Lys
  • Xaa at position 37 is Gly
  • Xaa at position 38 is Arg or is deleted
  • Xaa at position 39 is deleted and each of the other Xaa is the amino acid in the native form of GLP-1 (7-37) or (7-38).
  • Xaa at position 38 is Lys
  • Xaa at position 39 is Arg
  • each of the other Xaa is the amino acid in the native form of GLP-1 (7-39).
  • Xaa at position 26 is Arg, Gin, Glu, Asp, or His.
  • Xaa at position 34 is Arg, Glu, Asp, or His.
  • Xaa at position 7 is His
  • Xaa at position 8 is Ala
  • Xaa at position 7 is His
  • Xaa at position 8 is Thr, Ser, Gly or Val.
  • Xaa at position 7 is deleted. In some embodiments, Xaa at position 8 is Ala.
  • Xaa at position 8 is Thr, Ser, Gly or Val.
  • Xaa at position 7 is a modified amino acid.
  • Xaa at position 8 is Ala.
  • Xaa at position 8 is Thr, Ser, Gly or Val.
  • Xaa at position 18, 23 or 27 is Lys
  • Xaa at position 37 is Gly or is deleted
  • Xaa at position 38 is Arg or is deleted
  • Xaa at position 39 is deleted.
  • Xaa at position 36 is Lys
  • Xaa at position 37 is Gly
  • Xaa at position 38 is Arg
  • Xaa at position 39 is deleted.
  • Xaa at position 38 is Lys
  • Xaa at position 37 is Gly
  • Xaa at position 39 is Arg.
  • Xaa at position 34 is Lys
  • Xaa at position 37 is Gly or is deleted
  • Xaa at position 38 is Arg or is deleted
  • Xaa at position 39 is deleted.
  • Xaa at position 7 is His
  • Xaa at position 8 is Ala
  • Xaa at position 7 is His
  • Xaa at position 8 is Thr, Ser, Gly or Val.
  • Xaa at position 7 is deleted.
  • Xaa at position 8 is Ala.
  • Xaa at position 8 is Thr, Ser, Gly or Val.
  • Xaa at position 7 is a modified amino acid.
  • Xaa at position 8 is Ala.
  • Xaa at position 8 is Thr, Ser, Gly or Val.
  • Xaa at position 26 is Lys and
  • Xaa at position 34 is Arg, Glu, Asp, or His, and
  • the total number of different amino acids between the long-acting GLP-1 receptor agonist and the corresponding native form of GLP-l(7-36), (7-37) or (7-38) does not exceed three.
  • Xaa at position 7 is His
  • Xaa at position 8 is Ala
  • Xaa at position 7 is His
  • Xaa at position 8 is Thr, Ser, Gly or Val.
  • Xaa at position 7 is a modified amino acid.
  • Xaa at position 8 is Ala. In some embodiments, Xaa at position 8 is Thr, Ser, Gly or Val.
  • Xaa at position 7 is deleted.
  • Xaa at position 8 is Ala.
  • Xaa at position 8 is Thr, Ser, Gly or Val.
  • a long-acting GLP-1 receptor agonist of Formula III (SEQ ID NO:5), as described in U.S. Patent No. : 6,268,343:
  • the lipophilic substituent is (i) CH 3 (CH 2 )nCO- wherein n is 6, 8, 10, 12, 14, 16, 18, 20 or 22, (ii) HOOC(CH 2 )mCO- wherein m is 10, 12, 14, 16, 18, 20 or 22, or (iii) lithochoyl, and
  • the spacer is (i) an unbranched alkane ⁇ , ⁇ -dicarboxylic acid group having from 1 to 7 methylene groups, (ii) an amino acid residue except Cys, or (iii) ⁇ -aminobutanoyl.
  • the long-acting GLP-1 receptor agonist of Formula III wherein the lipophilic substituent is linked to the ⁇ -amino group of Lys via a spacer.
  • the spacer is ⁇ -glutamyl.
  • the spacer is ⁇ -asparagyl.
  • the spacer is glycyl.
  • the spacer is ⁇ -aminobutanoyl.
  • the spacer is ⁇ -alanyl.
  • the long-acting GLP-1 receptor agonist is Lys 26 (N e - tetradecanoyl), Arg 4 -GLP-l(7-37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e -(co-carboxynonadecanoyl)), Arg 4 -GLP-l(7-37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e -(co-carboxyheptadecanoyl)), Arg 4 -GLP-1(7- 37).
  • the long-acting GLP-1 receptor agonist is Lys 26 (N e -(co- carboxyundecanoyl)), Arg 4 -GLP-l(7-37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e -(co-carboxypentadecanoyl)), Arg 4 -GLP-l(7-37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e -lithochoyl),Arg 4 -GLP-l(7- 37).
  • the long-acting GLP-1 receptor agonist is Lys 26 (N e -(y-glutamyl(N a - hexadecanoyl))), Arg 4 -GLP- 1(7-37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e -(Yglutamyl(N a tetradecanoyl))), Arg 4 -GLP-l(7-37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e -(Yglutamyl(N a lithochoyl))), Arg 4 -GLP- 1(7-37).
  • the long-acting GLP-1 receptor agonist is Lys 26 (N e - (yglutamyl(N a octadecanoyl))), Arg 4 -GLP-l(7-37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e -decanoyl), Arg 4 -GLP-l(7-37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e -hexadecanoyl), Arg 4 -GLP- 1(7-37).
  • the long-acting GLP-1 receptor agonist is Lys 26 (N e -octanoyl), Arg 4 -GLP-1(7- 37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e -dodecanoyl), Arg 4 -GLP- 1(7-37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e (N 68 (Yaminobutyroyl-(NT-hexadecanoyl))), Arg 4 -GLP- 1(7-37).
  • the long-acting GLP-1 receptor agonist is Lys 26 (N e -(y-D- glutamyl(N a hexadecanoyl))), Arg 4 -GLP- 1(7-37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e -(Yglutamyl(N a -dodecanoyl))), Arg 4 -GLP- 1(7-37). In some embodiments, the GLP-1 derivative is Lys 26 (N e -( alanyl(N a -hexadecanoyl))), Arg 4 -GLP-1(7- 37).
  • the long-acting GLP-1 receptor agonist is Lys 26 (N e -(a- glutamyl(N a -hexadecanoyl))), Arg 4 -GLP-l(7-37). In some embodiments, the long-acting GLP-1 receptor agonist is Lys 26 (N e -(Y-glutamyl(N a -decanoyl))), Arg 4 -GLP- 1(7-37).
  • Semaglutide (Ozempic ® , developed and marketed by Novo Nordisk) is administered via weekly injection for treatment of type-2 diabetes.
  • the long-acting GLP-1 receptor agonist is semaglutide.
  • the long-acting GLP-1 receptor agonist is semaglutide that is co-formulated with insulin or an insulin analog.
  • the structure of semaglutide is based on liraglutide, with two further modifications: Gly in position 8 is replaced by Aib.
  • long-acting GLP-1 receptor agonist, semaglutide, of Formula IV (SEQ ID NO:6), as described in U.S. Patent No.: 8,129,343:
  • a long-acting GLP-1 receptor agonist of Formula V (SEQ ID NO:7), as described in U.S. Patent Nos.: 8,129,343 and 8,536,122:
  • Xaa7 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, ⁇ -hydroxy- histidine, homohistidine, N a -acety l-histidine, a-fluoromethyl-histidine, a-methyl-histidine, 3- pyridylalanine, 2-pyridylalanine, or 4-pyridylalanine; [00184] Xaas is Gly, Val, Leu, He, Lys, Aib, (1-aminocyclopropyl) carboxylic acid.
  • Xaai6 is Val or Leu
  • Xaais is Ser, Lys, or Arg
  • Xaai9 is Tyr or Gin
  • Xaa2o is Leu or Met
  • Xaa22 is Gly, Glu, or Aib;
  • Xaa23 is Gin, Glu, Lys, or Arg;
  • Xaa25 is Ala or Val
  • Xaa27 is Glu or Leu
  • Xaa3o is Ala, Glu, or Arg;
  • Xaa33 is Val or Lys
  • Xaa34 is Lys, Glu. Asn, or Arg;
  • Xaa35 is Gly or Aib
  • Xaa36 is Arg, Gly, Lys, or is absent;
  • Xaas7 is Gly, Ala, Glu, Pro, Lys, or is absent;
  • Xaa38 is Lys, Ser, amide, or is absent;
  • n 12, 13, 14, 15, 16, 17, or 18,
  • m is 0, 1, 2, 3, 4, 5, or 6,
  • s is 0, 1, 2. or 3
  • p is 3, 4. 5, 6, 7, 8. 9, 10, 11. 12, 13, 14. 15, 16, 17. 18, 19, 20. 21 , 22, or 23;
  • B is an acidic group selected from
  • Xaa7 is His or desamino-histidine
  • Xaa8 is Gly, Val, Leu, He, Lys or Aib;
  • Xaais is Ser
  • Xaai9 is Tyr
  • Xaa2o is Leu
  • Xaa22 is Gly, Glu or Aib;
  • Xaa23 is Gin or Glu
  • Xaa25 is Ala
  • Xaa27 is Glu
  • Xaa3o is Ala or Glu
  • Xaa33 is Val
  • Xaa34 is Lys or Arg
  • Xaa35 is Gly or Aib
  • Xaa36 is Arg or Lys
  • Xaa37 is Gly, amide or is absent
  • Xaa7 is His
  • Xaas is Gly, or Aib
  • Xaa1 ⁇ 2 is Val
  • Xaai9 is Tyr
  • Xaa2o is Leu
  • Xaa22 is Glu or Aib
  • Xaa23 is Gin
  • Xaa25 is Ala
  • Xaa27 is Glu
  • Xaa3o is Ala
  • Xaa33 is Val
  • Xaa34 is Lys or Arg
  • Xaa35 is Gly or Aib
  • Xaa37 is Gly
  • the long-acting GLP-1 receptor agonist of Formula V wherein said long-acting GLP-1 receptor agonist comprises Aib 8 .
  • the long-acting GLP-1 receptor agonist of Formula V wherein said long-acting GLP-1 receptor agonist comprises no more than six amino acid residues which have been exchanged, added or deleted as compared to GLP-l(7-37) set forth in the following sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 8).
  • the long-acting GLP-1 receptor agonist of Formula V wherein said long-acting GLP-1 receptor agonist comprises only one lysine residue.
  • the long-acting GLP-1 receptor agonist of Formula V which is Aib 8 , Arg 34 -GLP- 1(7-37) or Aib 8 - 22 , Arg 34 -GLP-l(7-37).
  • the long-acting GLP-1 receptor agonist of Formula V wherein U is a s acer selected from
  • ⁇ is
  • the long-acting GLP-1 receptor agonist having the following name: N-s 26 -[2-(2-[2-(2-[2-(2-[4-(17-Carboxyheptadecanoylamino)-4(S)- carboxybutyrylainino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP- l-(7-37)peptide.
  • HSA Human serum albumin
  • Albiglutide (Tanzeum ® ).
  • the long-acting GLP-1 receptor agonist is albiglutide, developed by GlaxoSmithKline (GSK).
  • Albiglutide includes two copies of GLP-1 fused as tandem repeat to the N-terminus of albumin. DPP-4-resistance is achieved by a single substitution, Ala for Gly, at the DPP-4 cleavage site. Albiglutide has a half-life of 6-8 days in humans.
  • Albiglutide has the following amino acid sequence (SEQ ID NO: 9):
  • HGEGTFTSDVS SYLEGQAAKEFIAWLVKGRHGEGTFTSDVSSYLEGQAAKEFIAWLVKGR
  • FC fusion Similar to albumin fusion, peptides can be linked to the constant region of immunoglobulin G (IgG), the Fc region.
  • IgG immunoglobulin G
  • the Fc region of IgG has a half-life of about 22 days.
  • Dulaglutide (Trulicity ® , Eli Lilly) is a recombinant fusion protein, which consists of two GLP-1 peptides covalently linked by a small peptide [tetraglycyl-L-seryltetraglycyl-L- seryltetraglycyl-Lseryl- L-alanyl (SEQ ID NO: 12)] to a human IgG4-Fc heavy chain variant.
  • the first 31 amino acids of dulaglutide are residues 3-37 of human GLP-1 with the following substitutions(relative to GLP-1 numbering): Ala8Gly, Gly22Glu, Arg36Gly to ensure protection from DPP-IV cleavage.
  • the next 16 amino acids are a linker sequence.
  • the remaining 228 amino acids are a synthetic human Fc fragment (immunoglobulin G4).
  • Two identical peptide chains form a dimer, linked by inter- monomer disulphide bonds between Cys55-55 and Cys58-58.
  • a long-acting GLP-1 receptor agonist, dulaglutide having the following amino acid sequence (SEQ ID NO. 10):
  • the nauseogenic compound is a long-acting GLP-1 receptor agonist selected from any of the compounds of Formula I, Formula II, Formula III, Formula IV, and Formula V.
  • the nauseogenic compound is a long-acting GLP- 1 receptor agonist of Formula I.
  • the nauseogenic compound is a long- acting GLP-1 receptor agonist of Formula II.
  • the nauseogenic compound is a long-acting GLP-1 receptor agonist of Formula III.
  • the nauseogenic compound is a long-acting GLP-1 receptor agonist of Formula IV.
  • the nauseogenic compound is a long-acting GLP-1 receptor agonist of Formula V.
  • the nauseogenic compound is a long-acting GLP-1 receptor agonist selected from any of the compounds of SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9, and SEQ ID NO. 10.
  • the nauseogenic compound is a long-acting GLP-1 receptor agonist of SEQ ID NO. 1.
  • the nauseogenic compound is a long-acting GLP-1 receptor agonist of SEQ ID NO. 2.
  • the nauseogenic compound is a long-acting GLP-1 receptor agonist of SEQ ID NO. 3. In some embodiments, the nauseogenic compound is a long-acting GLP-1 receptor agonist of SEQ ID NO. 4. In some embodiments, the nauseogenic compound is a long-acting GLP-1 receptor agonist of SEQ ID NO. 5. In some embodiments, the nauseogenic compound is a long-acting GLP-1 receptor agonist of SEQ ID NO. 6. In some embodiments, the nauseogenic compound is a long-acting GLP-1 receptor agonist of SEQ ID NO. 7. In some embodiments, the nauseogenic compound is a long-acting GLP-1 receptor agonist of SEQ ID NO. 8.
  • the nauseogenic compound is a long-acting GLP-1 receptor agonist of SEQ ID NO. 9. In some embodiments, the nauseogenic compound is a long-acting GLP-1 receptor agonist of SEQ ID NO. 10.
  • the area postrema was identified in the early 1950's as the locus of the chemoreceptor zone responsible for triggering vomiting.
  • the area postrema and adjacent structures within the dorsovagal complex, including the nucleus of the tractus solitaries (NTS) are rich in receptors for peptide hormones, and for gut peptides in particular.
  • Peptide pharmacologies identified at area postrema neurons include those listed below.
  • the nauseogenic peptide is selected from the group consisting of adrenomedullin, amylin, angiotensin II, atrial natriuretic peptide, cholecystokinin, chorionic gonadotropin leuteinizing hormone, corticotrophin releasing factor, endothelins, gastrin, ghrelin, glucagon, glucagon-like peptide 1 (GLP-1), insulin, insulin-like growth factor, leptin, leu-enkephalin, melanocortins, neurotensin, oxytocin, parathyroid hormones (e.g., PTH, PTHrP), pituitary adenylate cyclase activating peptide (PACAP), prolactin, prolactin releasing peptide, somatostatin, tachykinins (e.g., substance P), thyrotropin releasing hormone, va
  • the present invention provides formulations of drug particles suspended in a suspension vehicle for dispersion from a drug delivery device.
  • the suspension vehicle provides a stable environment in which the drug particle formulation is dispersed. Certain features of the drug particle and suspension vehicle are described in greater detail below.
  • the particle formulation typically comprises a drug (i.e. , the nauseogenic compound) and includes one or more stabilizing component (also referred to herein as "excipients").
  • stabilizing components include, but are not limited to, carbohydrates, antioxidants, amino acids, buffers, inorganic compounds, and surfactants.
  • the particle formulation may comprise about 50 wt % to about 90 wt % drug, about 50 wt % to about 85 wt % drug, about 55 wt % to about 90 wt % drug, about 60 wt % to about 90 wt % drug, about 65 wt % to about 85 wt % drug, about 65 wt % to about 90 wt % drug, about 70 wt % to about 90 wt % drug, about 70 wt % to about 85 wt % drug, about 70 wt % to about 80 wt % drug, or about 70 wt % to about 75 wt % drug.
  • a particle formulation comprises a drug, as described above, and one or more stabilizer.
  • the stabilizers may be, for example, carbohydrate, antioxidant, amino acid, buffer, inorganic compound, or surfactant.
  • the amounts of stabilizers in the particle formulation can be determined experimentally based on the activities of the stabilizers and the desired characteristics of the formulation, in view of the teachings of the present specification.
  • Suitable carbohydrates include disaccharides and/or non-reducing sugars, such as sucrose, trehalose, and raffinose.
  • antioxidants examples include, but are not limited to, methionine, ascorbic acid, sodium thiosulfate, catalase, platinum, ethylenediaminetetraacetic acid (EDTA), citric acid, cysteine, thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxanisol, butylated hydroxyltoluene, and propyl gallate.
  • amino acids that readily oxidize can be used as antioxidants, for example, cysteine, methionine, and tryptophan.
  • amino acids examples include, but are not limited to, arginine, methionine, glycine, histidine, alanine, L-leucine, glutamic acid, iso-leucine, L-threonine, 2-phenylamine, valine, norvaline, proline, phenylalanine, tryptophan, serine, asparagines, cysteine, tyrosine, lysine, and norleucine.
  • Suitable amino acids include those that readily oxidize, e.g., cysteine, methionine, and tryptophan.
  • buffers examples include, but are not limited to, citrate, histidine, succinate, phosphate, maleate, tris, acetate, carbohydrate, and gly-gly. Suitable buffers include citrate, histidine, succinate, and tris.
  • inorganic compounds that may be included in the particle formulation include, but are not limited to, NaCl, Na 2 S0 4 , NaHCCb, KC1, KH2PO4, CaCh, and MgCh.
  • the particle formulation may include other stabilizers/excipients, such as surfactants and salts.
  • surfactants include, but are not limited to, Polysorbate 20, Polysorbate 80, PLURONIC ® (BASF Corporation, Mount Olive, N.J.) F68, and sodium dodecyl sulfate (SDS).
  • salts include, but are not limited to, sodium chloride, calcium chloride, and magnesium chloride.
  • Drug particle formulations of the invention are preferably chemically and physically stable for at least 1 month, preferably at least 3 months, more preferably at least 6 months, more preferably at least 12 months at delivery temperature.
  • the delivery temperature is typically normal human body temperature, for example, about 37° C, or slightly higher, for example, about 40° C.
  • drug particle formulations of the present invention are preferably chemically and physically stable for at least 3 months, preferably at least 6 months, more preferably at least 12 months, at storage temperature. Examples of storage temperatures include refrigeration temperature, for example, about 5° C ; or room temperature, for example, about 25° C.
  • a drug particle formulation may be considered chemically stable if less than about 25%; preferably less than about 20%, more preferably less than about 15%, more preferably less than about 10%, and more preferably less than about 5% breakdown products of the drug particles are formed after about 3 months, preferably after about 6 months, preferably after about 12 months at delivery temperature of about 37° C and after about 6 months, after about 12 months, and preferably after about 24 months at storage temperature of about 5° C or about 25° C.
  • a drug particle formulation may be considered physically stable if less than about 10%, preferably less than about 5%, more preferably less than about 3%, more preferably less than 1% aggregates of the drug are formed after about 3 months, preferably after about 6 months, at delivery temperature and about 6 months, preferably about 12 months, at storage temperature.
  • the particles are typically sized such that they can be delivered via an implantable osmotic delivery device. Uniform shape and size of the particles typically helps to provide a consistent and uniform rate of release from such a delivery device; however, a particle preparation having a non-normal particle size distribution profile may also be used.
  • the size of the particles is less than about 30%, more preferably is less than about 20%, more preferably is less than about than 10%, of the diameter of the delivery orifice.
  • particle sizes may be, for example, less than about 150 microns to about 50 microns. In an embodiment of the particle formulation for use with an osmotic delivery system, wherein the delivery orifice diameter of the implant is about 0.1 mm, particle sizes may be, for example, less than about 30 microns to about 10 microns. In one embodiment, the orifice is about 0.25 mm (250 microns) and the particle size is about 2 microns to about 5 microns.
  • particles of a particle formulation have average diameters of about 1 micron to about 150 microns, e.g., less than 150 microns in diameter, less than 100 microns in diameter, less than 50 microns in diameter, less than 30 microns in diameter, less than 10 microns in diameter, less than 5 microns in diameter, and less than about 2 microns in diameter. In some embodiments, particles have average diameters of about 1 micron and about 50 microns. In some embodiments, particles of a particle formulation have average diameters of less than 1 micron.
  • Particles of a particle formulation comprising a nauseogenic compound may have average diameters, e.g., of about 0.3 microns to about 150 microns.
  • Particles of a particle formulation comprising an nauseogenic compound have average diameters of about 2 microns to about 150 microns, e.g., less than 150 microns in average diameter, less than 100 microns in average diameter, less than 50 microns in average diameter, less than 30 microns in average diameter, less than 10 microns in average diameter, less than 5 microns in average diameter, and about 2 microns in average diameter.
  • particles have average diameters of about 0.3 microns and 50 microns, for example, about 2 microns and about 50 microns. In some embodiments, the particles have an average diameter between 0.3 microns and 50 microns, for example, between about 2 microns and about 50 microns, where each particle is less than about 50 microns in diameter.
  • the particles of the particle formulations when incorporated in a suspension vehicle, do not settle in less than about 3 months, preferably do not settle in less than about 6 months, more preferably do not settle in less than about 12 months, more preferably do not settle in less than about 24 months at delivery temperature, and most preferably do not settle in less than about 36 months at delivery temperature of about 37° C.
  • the suspension vehicles typically have a viscosity of between about 5,000 to about 30,000 poise, preferably between about 8,000 to about 25,000 poise, more preferably between about 10,000 to about 20,000 poise. In one embodiment, the suspension vehicle has a viscosity of about 15,000 poise, plus or minus about 3,000 poise.
  • particles of about 2 microns to about 7 microns of the present invention will not settle for at least 20 years at room temperature based on simulation modeling studies.
  • particle formulation of the present invention for use in an implantable osmotic delivery device, comprises particles of sizes less than about 50 microns, more preferably less than about 10 microns, more preferably in a range from about 2 microns to about 7 microns.
  • particles of the particle formulations have a specific density that is substantially similar (e.g. , within 20%, 10%, 5%, 2% or 1%) to the specific density of the suspension vehicle to minimize separation (e.g. , floating or settling) of the particles from the suspension vehicle.
  • a drug particle formulation comprises a drug, as described above, one or more stabilizers, and optionally a buffer.
  • the stabilizers may be, for example, carbohydrate, antioxidant, amino acid, buffer, inorganic compound, or surfactant.
  • Preferred carbohydrates include disaccharides and/or non-reducing sugars, such as sucrose, trehalose, and raffinose.
  • antioxidants examples include, but are not limited to, methionine, ascorbic acid, sodium thiosulfate, catalase, platinum, ethylenediaminetetraacetic acid (EDTA), citric acid, cysteine, thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxanisol, butylated hydroxyltoluene, and propyl gallate.
  • amino acids that readily oxidize can be used as antioxidants, for example, cysteine, methionine, and tryptophan.
  • amino acids that may be included in the particle formulation include, but are not limited to, arginine, methionine, glycine, histidine, alanine, L-leucine, glutamic acid, iso-leucine, L-threonine, 2-phenylamine, valine, norvaline, praline, phenylalanine, tryptophan, serine, asparagines, cysteine, tyrosine, lysine, and norleucine.
  • buffers that may be included in the particle formulation include, but are not limited to, citrate, histidine, succinate, phosphate, maleate, tris, acetate, carbohydrate, and gly-gly.
  • inorganic compounds that may be included in the particle formulation include, but are not limited to, NaCl, Na 2 S0 4 , NaHCCb, KC1, KH2PO4, CaCh, and MgCh.
  • the particle formulation may include other excipients, such as surfactants, and salts.
  • surfactants include, but are not limited to, Polysorbate 20, Polysorbate 80, PLURONIC® (BASF Corporation, Mount Olive, N.J.) F68, and sodium dodecyl sulfate (SDS).
  • salts include, but are not limited to, sodium chloride, calcium chloride, and magnesium chloride.
  • All components included in the particle formulation are typically acceptable for pharmaceutical use in subjects, patients, mammals, particularly, in humans.
  • a selected drug or combination of drugs is formulated into dried powders in solid state, which preserve maximum chemical and biological stability of the drug.
  • the particle formulation offers long-term storage stability at high temperature, and therefore, allows delivery to a subject of stable and biologically effective drug for extended periods of time.
  • the suspension vehicle provides a stable environment in which the drug particle formulation is dispersed.
  • the drug particle formulations are chemically and physically stable (as described above) in the suspension vehicle.
  • the suspension vehicle typically comprises one or more polymer and one or more solvent that form a solution of sufficient viscosity to uniformly suspend the particles comprising the drug.
  • the suspension vehicle may comprise further components, including, but not limited to, surfactants, antioxidants, and/or other compounds soluble in the vehicle.
  • the viscosity of the suspension vehicle is typically sufficient to prevent the drug particle formulation from settling during storage and use in a method of delivery, for example, in an implantable, osmotic delivery device.
  • the suspension vehicle is biodegradable in that the suspension vehicle disintegrates or breaks down over a period of time in response to a biological environment, while the drug particle is dissolved in the biological environment and the active pharmaceutical ingredient (i.e., the drug) in the particle is absorbed.
  • the suspension vehicle is a "single-phase" suspension vehicle, which is a solid, semisolid, or liquid homogeneous system that is physically and chemically uniform throughout.
  • the solvent in which the polymer is dissolved may affect characteristics of the suspension formulation, such as the behavior of drug particle formulation during storage.
  • a solvent may be selected in combination with a polymer so that the resulting suspension vehicle exhibits phase separation upon contact with the aqueous environment.
  • the solvent may be selected in combination with the polymer so that the resulting suspension vehicle exhibits phase separation upon contact with the aqueous environment having less than approximately about 10% water.
  • the solvent may be an acceptable solvent that is not miscible with water.
  • the solvent may also be selected so that the polymer is soluble in the solvent at high concentrations, such as at a polymer concentration of greater than about 30%.
  • solvents useful in the practice of the present invention include, but are not limited to, lauryl alcohol, benzyl benzoate, benzyl alcohol, lauryl lactate, decanol (also called decyl alcohol), ethyl hexyl lactate, and long chain (Cs to C24) aliphatic alcohols, esters, or mixtures thereof.
  • the solvent used in the suspension vehicle may be "dry," in that it has a low moisture content.
  • Preferred solvents for use in formulation of the suspension vehicle include lauryl lactate, lauryl alcohol, benzyl benzoate, and mixtures thereof.
  • polymers for formulation of the suspension vehicles of the present invention include, but are not limited to, a polyester (e.g., polylactic acid and polylacticpolyglycolic acid), a polymer comprising pyrrolidones (e.g., polyvinylpyrrolidone having a molecular weight ranging from approximately 2,000 to approximately 1,000,000), ester or ether of an unsaturated alcohol (e.g., vinyl acetate), polyoxyethylenepolyoxypropylene block copolymer, or mixtures thereof.
  • Polyvinylpyrrolidone can be characterized by its K-value (e.g., K-17), which is a viscosity index.
  • the polymer is polyvinylpyrrolidone having a molecular weight of 2,000 to 1,000,000. In a preferred embodiment, the polymer is polyvinylpyrrolidone K-17 (typically having an approximate average molecular weight range of 7,900-10,800).
  • the polymer used in the suspension vehicle may include one or more different polymers or may include different grades of a single polymer. The polymer used in the suspension vehicle may also be dry or have a low moisture content. [00295]
  • a suspension vehicle for use in the present invention may vary in composition based on the desired performance characteristics.
  • the suspension vehicle may comprise about 40 wt % to about 80 wt % polymer(s) and about 20 wt % to about 60 wt % solvent(s).
  • Preferred embodiments of a suspension vehicle include vehicles formed of polymer(s) and solvent(s) combined at the following ratios: about 25 wt % solvent and about 75 wt % polymer; about 50 wt % solvent and about 50 wt % polymer; about 75 wt % solvent and about 25 wt % polymer.
  • the suspension vehicle may comprise selected components and in other embodiments consist essentially of selected components.
  • the suspension vehicle is typically formulated to provide a viscosity that maintains a uniform dispersion of the particle formulation for a predetermined period of time. This helps facilitate making a suspension formulation tailored to provide controlled delivery of the drug contained in the drug particle formulation.
  • the viscosity of the suspension vehicle may vary depending on the desired application, the size and type of the particle formulation, and the loading of the particle formulation in the suspension vehicle. The viscosity of the suspension vehicle may be varied by altering the type or relative amount of the solvent or polymer used.
  • the suspension vehicle may have a viscosity ranging from about 100 poise to about 1,000,000 poise, preferably from about 1,000 poise to about 100,000 poise.
  • the suspension vehicles typically have a viscosity, at 33° C, of between about 5,000 to about 30,000 poise, preferably between about 8,000 to about 25,000 poise, more preferably between about 10,000 to about 20,000 poise.
  • the suspension vehicle has a viscosity of about 15,000 poise, plus or minus about 3,000 poise, at 33° C. The viscosity may be measured at 33° C, at a shear rate of 10 "4 /sec, using a parallel plate rheometer.
  • the suspension vehicle may exhibit phase separation when contacted with the aqueous environment; however, typically the suspension vehicle exhibits substantially no phase separation as a function of temperature. For example, at a temperature ranging from approximately 0° C. to approximately 70° C. and upon temperature cycling, such as cycling from 4° C. to 37° C. to 4° C, the suspension vehicle typically exhibits no phase separation.
  • the suspension vehicle may be prepared by combining the polymer and the solvent under dry conditions, such as in a dry box.
  • the polymer and solvent may be combined at an elevated temperature, such as from approximately 40° C. to approximately 70° C, and allowed to liquefy and form the single phase.
  • the ingredients may be blended under vacuum to remove air bubbles produced from the dry ingredients.
  • the ingredients may be combined using a conventional mixer, such as a dual helix blade or similar mixer, set at a speed of approximately 40 rpm. However, higher speeds may also be used to mix the ingredients.
  • the suspension vehicle may be cooled to room temperature.
  • Differential scanning calorimetry (DSC) may be used to verify that the suspension vehicle is a single phase.
  • the components of the vehicle e.g., the solvent and/or the polymer
  • the drug particle formulation is added to the suspension vehicle to form a suspension formulation.
  • the suspension formulation may comprise a drug particle formulation and a suspension vehicle and in other embodiments consist essentially of a drug particle formulation and a suspension vehicle.
  • the suspension formulation may be prepared by dispersing the particle formulation in the suspension vehicle.
  • the suspension vehicle may be heated and the particle formulation added to the suspension vehicle under dry conditions.
  • the ingredients may be mixed under vacuum at an elevated temperature, such as from about 40° C. to about 70° C.
  • the ingredients may be mixed at a sufficient speed, such as from about 40 rpm to about 120 rpm, and for a sufficient amount of time, such as about 15 minutes, to achieve a uniform dispersion of the particle formulation in the suspension vehicle.
  • the mixer may be a dual helix blade or other suitable mixer.
  • the resulting mixture may be removed from the mixer, sealed in a dry container to prevent water from contaminating the suspension formulation, and allowed to cool to room temperature before further use, for example, loading into an implantable, drug delivery device, unit dose container, or multiple-dose container.
  • the suspension formulation typically has an overall moisture content of less than about 10 wt %, preferably less than about 5 wt %, and more preferably less than about 4 wt %.
  • the suspension formulations of the present invention are substantially homogeneous and flowable to provide delivery of the drug particle formulation from the osmotic delivery device to the subject.
  • the components of the suspension vehicle provide biocompatibility.
  • Components of the suspension vehicle offer suitable chemico-physical properties to form stable suspensions of drug particle formulations. These properties include, but are not limited to, the following: viscosity of the suspension; purity of the vehicle; residual moisture of the vehicle; density of the vehicle; compatibility with the dry powders; compatibility with implantable devices; molecular weight of the polymer; stability of the vehicle; and hydrophobicity and hydrophilicity of the vehicle. These properties can be manipulated and controlled, for example, by variation of the vehicle composition and manipulation of the ratio of components used in the suspension vehicle.
  • suspension formulations described herein may be used in an implantable delivery device, including any of those described herein.
  • suspension formulations described herein may be used in an implantable, osmotic delivery device to provide zero-order, continuous, controlled, and sustained delivery of a compound over an extended period of time, such as over weeks, months, or up to about one year or more.
  • Such an implantable osmotic delivery device is typically capable of delivering the suspension formulation, comprising the drug, at a desired flow rate over a desired period of time.
  • the suspension formulation may be loaded into the implantable, osmotic delivery device by conventional techniques.
  • the implantable, osmotic delivery device typically includes a reservoir having at least one orifice through which the suspension formulation is delivered.
  • the suspension formulation may be stored within the reservoir.
  • the implantable, drug delivery device is an osmotic delivery device, wherein delivery of the drug is osmotically driven.
  • the osmotic delivery device typically consists of a cylindrical reservoir which contains the osmotic engine, piston, and drug formulation.
  • the reservoir is capped at one end by a controlled-rate, semi-permeable membrane and capped at the other end by a diffusion moderator through which suspension formulation, comprising the drug, is released from the drug reservoir.
  • the piston separates the drug formulation from the osmotic engine and utilizes a seal to prevent the water in the osmotic engine compartment from entering the drug reservoir.
  • the diffusion moderator is designed, in conjunction with the drug formulation, to prevent body fluid from entering the drug reservoir through the orifice.
  • the osmotic device releases a drug at a predetermined rate based on the principle of osmosis.
  • Extracellular fluid enters the osmotic delivery device through a semi -permeable membrane directly into a salt engine that expands to drive the piston at a slow and even delivery rate. Movement of the piston forces the drug formulation to be released through the orifice or exit port at a predetermined sheer rate.
  • the reservoir of the osmotic device is loaded with a suspension formulation wherein the device is capable of delivering the suspension formulation to a subject over an extended period of time (e.g., about 1, about 3, about 6, about 9, about 10, and about 12 months) at a pre-determined, therapeutically effective delivery rate.
  • the release rate of the drug from the osmotic delivery device typically provides a subject with a predetermined target dose of a drug, for example, a therapeutically effective daily dose delivered over the course of a day; that is, the release rate of the drug from the device, provides substantial steady-state delivery of the drug at a therapeutic concentration to the subject.
  • a predetermined target dose of a drug for example, a therapeutically effective daily dose delivered over the course of a day; that is, the release rate of the drug from the device, provides substantial steady-state delivery of the drug at a therapeutic concentration to the subject.
  • the volume of a beneficial agent chamber comprising the beneficial agent formulation is between about 100 ⁇ to about 1000 ⁇ , more preferably between about 120 ⁇ and about 500 ⁇ , more preferably between about 150 ⁇ and about 200 ⁇ .
  • the osmotic delivery device is implanted within the subject, for example, subdermally or subcutaneously to provide subcutaneous drug delivery.
  • the device(s) can be implanted subdermally or subcutaneously into either or both arms (e.g., in the inside, outside, or back of the upper arm) or the abdomen.
  • Preferred locations in the abdominal area are under the abdominal skin in the area extending below the ribs and above the belt line.
  • the abdominal wall can be divided into 4 quadrants as follows: the upper right quadrant extending at least 2-3 centimeters below the right ribs, e.g.
  • the lower right quadrant extending at least 2-3 centimeters above the belt line, e.g. , at least about 5-8 centimeters above the belt line, and at least 2-3 centimeters to the right of the midline, e.g. , at least about 5-8 centimeters to the right of the midline; the upper left quadrant extending at least 2-3 centimeters below the left ribs, e.g.
  • Termination of treatment by removal of an osmotic delivery device from a subject is straightforward, and provides the important advantage of immediate cessation of delivery of the drug to the subject.
  • the osmotic delivery device has a fail-safe mechanism to prevent an inadvertent excess or bolus delivery of drug in a theoretical situation like the plugging or clogging of the outlet (diffusion moderator) through which the drug formulation is delivered.
  • the osmotic delivery device is designed and constructed such that the pressure needed to partially or wholly dislodge or expel the diffusion moderator from the reservoir exceeds the pressure needed to partially or wholly dislodge or expel the semi-permeable membrane to the extent necessary to de-pressurize the reservoir.
  • suspension formulations may also be used in infusion pumps, for example, the ALZET® (DURECT Corporation, Cupertino, Calif.) osmotic pumps which are miniature, infusion pumps for the continuous dosing of laboratory animals (e.g., mice and rats).
  • ALZET® DURECT Corporation, Cupertino, Calif.
  • osmotic pumps which are miniature, infusion pumps for the continuous dosing of laboratory animals (e.g., mice and rats).
  • the suspension formulations described herein may be used in an non-implantable delivery device, including any of those described herein.
  • the non- implantable delivery device is a miniaturized patch pump placed on the surface of the skin, such as e.g. , JewelPUMPTM (Debiotech S.A.). Dosing of the JewelPUMPTM device is adjustable and programmable. As such, mean steady state concentration (Css) in plasma of a nauseogenic compound can gradually be attained, via slow ramp-up of an increasing dosage, or via continuous administration of a fixed dose, in the subject over days, weeks or months.
  • Css steady state concentration
  • the jewelPUMPTM is based on a microelectromechanical system (MEMS) integrated and ultra-precise disposable pump-chip technology.
  • the jewelPUMPTM is a miniaturized patch- pump with a disposable unit having payload for administration of compound.
  • the disposable unit is filled once with compound and discarded after use, while the controller unit (including the electronics) can be used for 2 years with multiple disposable units.
  • the jewelPUMPTM is detachable, watertight for bathing and swimming, includes direct access bolus buttons and a discreet vibration & audio alarm on the patch-pump.
  • the jewelPUMPTM is remotely controlled.
  • the above drugs and other drugs known to those of skill in the art are useful in methods of treatment for a "variety of conditions" including but not limited to the following: chronic pain, hemophilia and other blood disorders, endocrine disorders, metabolic disorders, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Alzheimer's disease, cardiovascular diseases (e.g.
  • diabetes including type 1, type 2 diabetes mellitus, human immunodeficiency virus treatment-induced, latent autoimmune diabetes in adults, and steroid-induced
  • obesity hypoglycemia unawareness, restrictive lung disease, chronic obstructive pulmonary disease, lipoatrophy, metabolic syndrome, leukemia, hepatitis, renal failure, infectious diseases (including bacterial infection, viral infection (e.g., infection by human immunodeficiency virus, hepatitis C virus, hepatitis B virus, yellow fever virus, West Nile virus, Dengue virus, Marburg virus, and Ebola virus), and parasitic infection), hereditary diseases (such as cerebrosidase deficiency and adenosine deaminase deficiency), hypertension, septic shock, autoimmune diseases (e.g., Grave's disease, systemic lupus erythematosus, multiple sclerosis,
  • FIGs 2 - 8 describe predicted plasma concentrations for different GLP-1 agonists dosed according to prescribers' information.
  • Plasma concentrations are each expressed as a fraction of peak plasma concentration i.e., steady state concentration (Css).
  • the predictions are based upon published human pharmacokinetic data, with either raw plasma concentration data or data digitized from published figures for a single subcutaneous dose.
  • the plasma concentrations were fitted to a model describing "absorption + single component decay" for each agent, as depicted in Figure 13, based upon a rate constant for absorption from a subcutaneous depot into the plasma, and another rate constant for elimination from the plasma compartment. Data were fit using non-linear regression via an iterative least-squares method within Prism v7.0 (GraphPad Software Inc., San Diego, CA).
  • the derived plasma concentration profile for a single subcutaneous bolus was extended from the time of dosing until plasma concentrations were negligible. This profile was serially added to itself, staggered by a period determined by the indicated dose interval, and in a magnitude determined by the recommended dose increases. The numeric sum is shown as the black line in each plot.
  • Rate of change of drug concentration was derived as the first differential of the plasma concentration profile summed as described above.
  • the d[drug]/dt was expressed with "dtdrug]" units reduced to percent of steady state mean concentration of indicated doses, to enable comparisons between agents with differing potencies and pharmacokinetics.
  • the "df ' units were hours.
  • the X-axes in Figures 10 and 12 represent the d[drug]/dt thus obtained, in units of "% of steady-state mean (i.e., Css) per hour".
  • GLP-1 receptors were transiently expressed in cultured CHO-K1 cells: 1 x 10 6 CHO-K1 cells were seeded in T75 flasks and cultured in maintenance media for 48 hours prior to transfecting with GLP-1 receptor expression constructs.
  • GLPlR-containing plasmid DNA was mixed with OptiMEMl and Lipofectamine 2000 and incubated at room temperature for 20 minutes before addition directly to CHO-K1 cells following a single wash- aspirate step with IX DPBS +/+. Cells were incubated 48 hours at 37°C, 5% CO2 to allow for receptor expression.
  • a 10 "4 M stock of each test peptide was diluted to a concentration of 2 x 10 "7 M in stimulation buffer and then serially diluted with stimulation buffer 10-fold to generate 2X peptide working concentrations ranging from 2 x 10 "7 M down to 2 x 10 "17 M.
  • hGLPlR-expressing CHO-K1 cells were washed and aspirated once with IX DPBS -/-. Cells were dissociated and further incubated before repeated (20x) pipetting to create a uniform suspension, which was then counted using a Cellometer mini (Nexcelom Bioscience). Suspensions were centrifuged at 150 x g for five minutes, supernatant removed, and then re-suspended to a density of 1 x 10 5 cells per milliliter in stimulation buffer.
  • a decrease in potency upon exposure of a nauseogenic peptide to 4% albumin is contemplated to correlate to reductions in the incidence and/or prevalence of nausea upon continuous administration of the nauseogenic peptide according to methods described herein.
  • nauseogenic compounds are known to mediate their effects via activation of neurons at the area postrema, a brainstem structure that senses nutrients, meal-related peptides and other chemical signals. The same structure mediates the anorectic effects of these same peptide and nutrient stimuli. Dogs, a species that normally vomits, no longer vomit when the area postrema has been surgically ablated. In other species, control of food intake in response to nutrients and meal-related peptides is also impaired when area postrema is ablated. Thus, satiety, anorexia, nausea and vomiting may be considered as a continuum of responses mediated via a common anatomic structure. Alterations in the pattern of one response may reasonably be expected to map alterations in the pattern of another.
  • Data can be analyzed as a cumulative effect, or as an instantaneous effect (within a single time "bin").
  • pramlintide an amylin agonist
  • peptide is infused intravenously for 1 hour at a total dose of 0.033 mg/kg.
  • Sample is mixed with 25 ⁇ ⁇ 2 ⁇ , protease inhibitor cocktail.
  • the 1 hour sample is taken before cessation of intravenous peptide infusion.
  • There are n 3 animals per group.

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EP18712409.4A 2017-03-08 2018-03-08 Vorrichtung und verfahren zur verabreichung einer nauseogenen verbindung aus einer arzneimittelabgabevorrichtung Pending EP3592376A1 (de)

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Family Cites Families (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5609885A (en) 1992-09-15 1997-03-11 Alza Corporation Osmotic membrane and delivery device
US6395292B2 (en) 1996-02-02 2002-05-28 Alza Corporation Sustained delivery of an active agent using an implantable system
DK1238657T3 (da) 1996-02-02 2005-01-17 Alza Corp Vedvarende frigivelse af et aktivt middel ved anvendelse af et implanterbart system
US6156331A (en) 1996-02-02 2000-12-05 Alza Corporation Sustained delivery of an active agent using an implantable system
US6132420A (en) 1996-02-02 2000-10-17 Alza Corporation Osmotic delivery system and method for enhancing start-up and performance of osmotic delivery systems
US6261584B1 (en) 1996-02-02 2001-07-17 Alza Corporation Sustained delivery of an active agent using an implantable system
US6268343B1 (en) 1996-08-30 2001-07-31 Novo Nordisk A/S Derivatives of GLP-1 analogs
US7235627B2 (en) 1996-08-30 2007-06-26 Novo Nordisk A/S Derivatives of GLP-1 analogs
ZA981610B (en) 1997-03-24 1999-08-26 Alza Corp Self adjustable exit port.
MY125849A (en) 1997-07-25 2006-08-30 Alza Corp Osmotic delivery system, osmotic delivery system semipermeable body assembly, and method for controlling delivery rate of beneficial agents from osmotic delivery systems
CN100388916C (zh) 1997-12-22 2008-05-21 阿尔扎有限公司 用于控释药物传递装置的速率控制膜
WO1999033446A1 (en) 1997-12-29 1999-07-08 Alza Corporation Osmotic delivery system with membrane plug retention mechanism
PT1041974E (pt) 1997-12-30 2007-01-31 Alza Corp Sistema de entrega de agente benéfico como obturador de membrana
ATE466027T1 (de) * 1998-02-27 2010-05-15 Novo Nordisk As Abkömmlinge von glp-1 analogen
CA2356860C (en) 1998-12-31 2006-11-07 Alza Corporation Osmotic delivery system having space efficient piston
US6528486B1 (en) 1999-07-12 2003-03-04 Zealand Pharma A/S Peptide agonists of GLP-1 activity
ATE306908T1 (de) 1999-12-21 2005-11-15 Alza Corp Ventil für osmotische vorrichtungen
US7163688B2 (en) 2001-06-22 2007-01-16 Alza Corporation Osmotic implant with membrane and membrane retention means
CA2490544C (en) 2002-06-26 2011-04-19 Alza Corporation Minimally compliant, volume efficient piston for osmotic drug delivery systems
US7014636B2 (en) 2002-11-21 2006-03-21 Alza Corporation Osmotic delivery device having a two-way valve and a dynamically self-adjusting flow channel
AU2004227985B2 (en) 2003-03-31 2009-04-02 Intarcia Therapeutics, Inc. Osmotic pump with means for dissipating internal pressure
US20050175701A1 (en) 2004-02-10 2005-08-11 Alza Corporation Capillary moderator for osmotic delivery system
US7456254B2 (en) 2004-04-15 2008-11-25 Alkermes, Inc. Polymer-based sustained release device
TWI362392B (en) 2005-03-18 2012-04-21 Novo Nordisk As Acylated glp-1 compounds
US20070027105A1 (en) 2005-07-26 2007-02-01 Alza Corporation Peroxide removal from drug delivery vehicle
JP5693817B2 (ja) 2005-08-19 2015-04-01 アミリン・ファーマシューティカルズ, リミテッド・ライアビリティ・カンパニーAmylin Pharmaceuticals, Llc 糖尿病の治療法および体重の減少法
AU2007266475B2 (en) 2006-05-30 2009-12-03 Intarcia Therapeutics, Inc. Two-piece, internal-channel osmotic delivery system flow modulator
AU2007284759B2 (en) 2006-08-09 2010-10-28 Intarcia Therapeutics, Inc. Osmotic delivery systems and piston assemblies
WO2008061355A1 (en) * 2006-11-24 2008-05-29 Matregen Corp. Glp-1 depot systems, and methods of manufacture and uses thereof
DK2240155T3 (da) 2008-02-13 2012-09-17 Intarcia Therapeutics Inc Indretninger, formuleringer og fremgangsmåder til levering af flere gavnlige midler
MX352878B (es) * 2009-09-28 2017-12-13 Intarcia Therapeutics Inc Establecimiento y/o terminacion rapidos de suministro de estado estable sustancial de farmaco.
EP3000482B1 (de) * 2009-12-16 2021-04-21 Novo Nordisk A/S Zweifach acylierte glp-1-derivate
US20120208755A1 (en) * 2011-02-16 2012-08-16 Intarcia Therapeutics, Inc. Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers
US8575091B1 (en) 2012-04-19 2013-11-05 Novo Nordisk A/S Amylin analogues and pharmaceutical compositions thereof
TW201534616A (zh) 2013-05-02 2015-09-16 Glaxosmithkline Ip Dev Ltd 治療性胜肽

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